AU2009350857A1 - Conformationally constrained, fully synthetic macrocyclic compounds - Google Patents

Conformationally constrained, fully synthetic macrocyclic compounds Download PDF

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AU2009350857A1
AU2009350857A1 AU2009350857A AU2009350857A AU2009350857A1 AU 2009350857 A1 AU2009350857 A1 AU 2009350857A1 AU 2009350857 A AU2009350857 A AU 2009350857A AU 2009350857 A AU2009350857 A AU 2009350857A AU 2009350857 A1 AU2009350857 A1 AU 2009350857A1
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acid
amino
alo
pct
heteroaryl
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Philipp Ermert
Franck Lach
Anatol Luther
Karsten Marx
Kerstin Mohle
Daniel Obrecht
Said Oumouch
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Spexis AG
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Polyphor AG
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Abstract

Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of type (I) are constituted by three distinct building blocks: an aromatic template a, a conformation modulator b and a spacer moiety c as detailed in the description and the claims. Macrocycles of type (I) are readily manufactured by parallel synthesis or combinatorial chemistry. They are designed to interact with specific biological targets. In particular, they show agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT (5-HT receptor), and on the prostaglandin F2 • receptor (FP receptor). They are thus potentially useful for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis and constipation type irritable bowl syndrome; of CNS related diseases like migraine, schizophrenia, psychosis or depression; of ocular hypertension such as associated with glaucoma and preterm labour.

Description

WO 2011/015241 PCT/EP2009/060168 1 Conformationally constrained, fully synthetic macrocyclic compounds Macrocyclic natural and synthetic products have played a 5 crucial role in the development of new drugs, especially as anti-infectives (see Review: F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Hdbich, Angew. Chem. Int. Ed. Engl. 2006, 45, 5072-5129; D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J. DeMarco, K. Moehle, F. 0. Gombert, Curr. Med. 10 Chem. 2009, 16, 42-65), as anti-cancer drugs and in other therapeutic areas (C. E. Ballard, H. Yu, B. Wang, Curr. Med. Chem. 2002, 9, 471-498; F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Herrera, Curr. Med. Chem. 2004, 11, 1309-1332). They often display remarkable biological activities, and many 15 macrocycles or their derivatives have been successfully developed into drugs (L. A. Wessjohann, E. Ruijter, D. Garcia Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186; D. J. Newman, G. M. Gragg, K. M. Snader, J. Nat. Prod. 2003, 66, 1022-1037) The chemical diversity of macrocyclic natural products is 20 immense and provides a tremendous source of inspiration for drug design. Macrocyclic natural and synthetic products generally exhibit semi-rigid backbone conformations placing appended substituents 25 in well-defined positions in space. Certain ring sizes are preferred (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186), e.g. 16-membered rings are frequently found in oxygen-containing macrocycles, such as polyketides (M. Q. Zhang, B. Wilkinson, Curr. Opin. Biotechnol. 30 2007, 18, 478-488). It is hypothesized that the semi-rigid scaffolds may possess some of the favorable binding properties of rigid molecules (entropy), yet still retaining enough flexibility to adapt suitable conformations in the binding event (induced fit). 35 WO 2011/015241 PCT/EP2009/060168 2 Macrocyclic natural and synthetic products are generally classified according to the chemical nature of the backbone, e.g. cyclic peptides (Y. Hamady, T. Shioiri, Chem. Rev. 2005, 105, 4441-4482; N.-H. Tan, J. Zhou, Chem. Rev. 2006, 106, 840 5 895); cyclic depsipeptides (F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Herrera, Curr. Med. Chem. 2004, 11, 1309 1332); macrocyclic lactones (macrolactones) and macrolides; macrocyclic lactams, macrocyclic amines, macrocyclic ethers, macrocyclic ureas and urethanes, and others. The 10 conformational, physico-chemical, pharmacological and pharmacodynamic properties of macrocyclic natural and synthetic compounds depend largely on the ring size, the chemical nature of the backbone, and of appended groups (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 15 171-186). By modifying these three parameters nature has generated a virtually unlimited repertoire of molecular diversity. Despite their undisputed interesting biological properties, natural products show some limitations for drug development, such as: 20 - High structural complexity - Metabolic instability - Low oral bioavailability - Low membrane permeability; intracellular targets not 25 amenable - Low tissue penetration - Short half-life - Chemical synthesis often very complex and lengthy - Often accessible only by fermentation or recombinant 30 methods - High production costs - Complex QC and development processes. Broadly speeking, the present invention describes novel, fully 35 synthetic, macrocyclic natural product-like molecules of type I, which can be synthesized e.g. by connecting suitably WO 2011/015241 PCT/EP2009/060168 3 protected building blocks A, B, and C in a modular fashion to a linear precursor followed by subsequent cyclization (Scheme 1). Scheme 1: Summary of the invention Building Blocks A "Template" O X RR1 xx 0 a Building Blocks B "Modulator"
R
4 -N R 3 Building Blocks C "Bridge" -NN NR4, U 5 Building blocks A serve as conformation-inducing templates and are based on appropriately substituted (R2) and protected phenolic or thiophenolic aromatic carboxylic acids. 10 Building blocks B are appropriately substituted (R2, R') and protected tertiary amino alcohols, preferably derived from an amino acid such as substituted proline, substituted pipecolic acid or substituted piperazine-2-carboxylic acid. Building blocks B are linked to building block A via an ether (X=O) or 15 thioether (X=S) bond and to building block C via a secondary or WO 2011/015241 PCT/EP2009/060168 4 tertiary amide bond. The sulfur atom of a thioether linkage can easily and selectively be oxidized to the corresponding sulfoxide (S=0) or sulfone (S(=0)2) which forms part of the invention. Importantly, the amide bond between modulator B and 5 spacer C can also be part of an extended connector moiety U. For example in the case of a standard amide bond, U corresponds to a carbonyl group (-C(=0)-). If U is defined as a carbamoyl moiety (-NR4-C(=0)-) the functional connection between B and C corresponds to a urea moiety. Similarly a carboxyl group (-0 10 C(=0)-) as U describes a carbamate linkage between B and C. In addition, U can represent an oxalyl group (-C(=0)-C(=0)-) or the corresponding acetal (-C(-OR 2 0
)
2 -C(=0)-). Importantly, in the case that R2 of building block B 15 constitutes an amine substituent, an alternative incorporation into the macrocyclic ring via the exocyclic amine functionality is possible: b R 3 '1 R 4 This alternative binding mode is also part of the invention. 20 Building blocks B serve as a conformational modulator by influencing the conformation of the macrocycle through cis/trans-isomerization of the amide bond. 25 In molecules of type I the building blocks A and B are connected via the bridges C; the structural element C is linked to A by a secondary or tertiary amide bond. The bridge C can be constituted by one to three appropriately and independently substituted (R 4
-R
0 ; R 4 -") subunits cl-c3 derived from suitably 30 substituted and protected precursors, most often from, but not limited to, appropriately substituted and protected amino acid WO 2011/015241 PCT/EP2009/060168 5 derivatives or suitably substituted and protected amine derivatives. N U C = R41 R4 i.e. R4c V U or 4N W U R4R4 0 0R 4 N VO W 0.-1 0-1 V,vv= .- R 4 R R R R R U 0 0 0 OR 2 0 N 0 0R, 5 These subunits cl-c3 are in turn independently connected to each other by an amide bond (-C(=O)NR 4 _), a methylene heteroatom linkage (-CHR 3 -Z-), an alkene[1,2]diyl moiety (-CHR"=CHR 3-) , introduced by olefin metathesis, an alkane[1,2]diyl spacer (-CHR 2 -CHR-), accessible from the 10 metathesis product by hydrogenation, an oxalyl group (-C(=O) C(=O)-) or a disulfide bridge (-S-S-). The spatial orientation of the substituents R -R 9 in compounds of type I is modulated by the ring size and the stereochemical 15 connectivity within building blocks A, B and C. Both, the macrocyclic backbone and the substituents R-R1 3 can contribute to the biological activity of compounds of type I. The backbone of the compounds of type I is composed of an 20 aromatic ether/thioether linkage and one or more tertiary amide bonds; in some cases an aliphatic ether linkage, an ethylidene or an ethylene moiety may also be part of the backbone as defined above. Ether linkages in macrocyclic molecules have been shown to be beneficial by favorably influencing physico 25 chemical and pharmacological properties, such as e.g.
WO 2011/015241 PCT/EP2009/060168 6 solubility in water, metabolic stability towards proteolytic degradation, cell permeability and oral absorption (K. X. Chen et al., J. Med. Chem. 2006, 49, 995-1005). In addition, tertiary amide containing macrocycles show increased 5 proteolytic stability, cell permeability and oral bioavailability compared to the parent molecules with secondary amide bonds (E. Biron, J. Chatterjee, 0. Ovadia, D. Langenegger, J. Brueggen, D. Hoyer, H. A. Schmid, R. Jelinek, C. Gilon, A. Hoffmann, H. Kessler, Angew. Chem. Int. Ed. 2008, 10 47, 1-6; J. Chatterjee, 0. Ovadia, G. Zahn, L. Marinelli, A. Hoffmann, C. Gilon, H. Kessler, J. Med. Chem. 2007, 50, 5878 5881). For example, the cyclic undecapeptide cyclosporin A (INN: Ciclosporin), which is used as immunosuppressant in organ transplants, contains seven N-methylated amino acids and 15 possesses good oral bioavailability when formulated appropriately (P. R. Beauchesne, N. S. C. Chung, K. M. Wasan, Drug Develop. Ind. Pharm. 2007, 33, 211-220). Peptidyl cis/trans isomerization of proline and pipecolic acid containing polypeptides and proteins is a well known process in 20 protein folding events. In vivo, this process can be mediated by peptidyl prolyl cis/trans isomerases such as the cyclophilins, the FK506-binding proteins and the parvulins (A. Bell, P. Monaghan, A. P. Page, Int. J. Parasitol. 2006, 36, 261-276). Besides their role in protein folding and in the 25 immune system, peptidyl prolyl cis/trans isomerases have been implicated in cell cycle control (P. E. Shaw, EMBO Reports 2002, 3, 521-526) and therefore constitute interesting pharmaceutical targets. FK506 and cyclosporin A which bind to the FK506-binding protein and cyclophilins, respectively, are 30 both macrocyclic natural products, with the former one containing a pipecolic acid residue. For many existing and emerging biological targets it is difficult to find classical small molecule hits as starting points for drug development (J. A. Robinson, S. DeMarco, F. 35 Gombert, K. Moehie, D. Obrecht, Drug Disc. Today 2008, 13, 944 951). Many of these extra- and intracellular "difficult WO 2011/015241 PCT/EP2009/060168 7 targets" involve protein-protein interactions, such as receptor tyrosine kinases, growth factor receptors, transcriptional activators/transcription factors, chaperones, and others. For several of them macrocyclic natural and synthetic compounds 5 have been described as good starting points for drug discovery programs (e.g. D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J. DeMarco, K. Moehle, F. 0. Gombert, Curr. Med. Chem. 2009, 16, 42-65). The novel and fully synthetic macrocyclic compounds of type I 10 described in this invention combine unique features of macrocyclic natural products with beneficial physico-chemical and pharmacological properties of traditional small molecules, like: - Natural product-like structural complexity 15 - Good solubility - High metabolic stability - Improved oral bioavailability - Improved membrane permeability - Extra- and intracellular targets amenable 20 - Improved tissue penetration - Small molecule-like pharmacokinetics - Modular chemical synthesis - Synthesis process amenable to parallelization - Reasonable production costs 25 - Small molecule-like QC and development processes WO 2011/015241 PCT/EP2009/060168 8 More particularly, the present invention provides macrocyclic compounds of the general formula I (Figure 2), which are comprised of building blocks of general formulae A, B and C as depicted in Scheme 2 below. 5 Scheme 2: Compounds of type I and building blocks A, B and C RI A 0 a N ~'R3 r N 1 R4- R3 RR b r2 N -V W < U 01 0-1 With respect to the building blocks A, B and C, the encircled 10 moieties, i.e. a in A, b in B and cl-c3 in C, shall represent their most basic skeletons appropriately and independently substituted as is detailed later on. The basic skeletons of a and b correspond to the ring systems depicted in Table 1 and Table 2. 15 Table 1: Ring Systems al-a25 of Building Blocks A N N al a2 a3 a4 NN a5 a6 a7 a8 WO 2011/015241 PCT/EP2009/060168 9 JNN S Y N Y N-. Y a9 alO all a12 N N N I> IN a13 a14 a15 a16 N N a17 a18 a19 a20 N N N N N ,NN 0 a21 a22 a23 a24 a25 Table 2: Ring Systems b1-bl of Building Blocks B ,,N NO,, b1 b2 b3 b4 NN ',N b5 b6 b7 b8 WO 2011/015241 PCT/EP2009/060168 10 b9 blO b11 Depending on the substitution pattern of skeletons b alternative binding modes are feasible. For skeletons b3 and b4 such incorporation via the exocyclic nitrogen atom is 5 represented by the following two structures, which form part of the invention: ,R3 R R3 N-R11 N'R11 -- NN 4 F 4 The encircled parts of the bridge subunits cl-c3 represent 10 optionally substituted groups. Definitions of cl-c3 are exemplified in Table 3, each reading from the N-terminus to the C-terminus of the linker C. In the simplest case the linker C is constituted by one subunit c1, i.e. cl-1 to cl-6. For the embodiments consisting of two or three subunits all possible 15 combinations of the subunits cl-c3 and the connectivities U, V and W are part of the invention. Table 3: Scope of Subunits cl-c3 of the Linker Group C 0 0 0 o oj o R4, -V W= U U1 OR20 CR200 00 OW R3 R1 2
R
13
R
12
R
13 0 0 V, W= N' R s-s WO 2011/015241 PCT/EP2009/060168 11
R
5
R
5 R14 R14 R 5 _ 0__--C--C--- -- C--C- ~e ~is [15 '6 6 RR1 Rio RS 1-2 1-2 c1-1 cl-2 cl-3
R
14
R
5
R
14
R
5 R14 R14 RS 1 1
R
6 R 1 Re R1 R15 R 6 3-5 3-5 cl-4 cl-5 cl-6 7 7 [R16R16 1 p 7 __6_ - -C--}C-- - C-- C- -a R8 R17
R
17
R
8 1-2 1-2 c2-1 c2-2 c2-3 c2 ________
R
16 R R R 7 7 R16 R 16 p 7 R 1 I I1 1 --- --- -C-- - R 8 17 8 17 R8 - 17 - 17 - 8 3-5 3-5 c2-4 c2-5 c2-6
R
9
R
9
R
16
R
16
R
9 - --C-- C-- --- C-C- c3 1 0
R
1 0 p 17
R
17
P
10 c3-1 c3-2 c3-3 The substituents directly attached to the basic skeletons containing building block A, B and C, i.e. R'-R", are defined 5 as follows: R : H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF2; NO 9 ; CN; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 10 - (CR1 8 R"1) qOR 20 ; - (CR"RI') qSR 20 ; - (CR'R') qNR 4 R2; WO 2011/015241 PCT/EP2009/060168 12 - (CR' R") qOCONRR"; - (CR"R") 4 OCOOR'; - (CR' R") 0 NR'COOR'; - (CR' R") qNR'COR1, - (CR'R ') NR'CONRR" ; - (CR' R") qNR 4 SO2R23; - (CR R") qNR'SONR'R"; - (CR'R") qCOOR ; - (CR'R") gCONR'R"; - (CR' R") qSO2NR'R"; - (CR"R") qPO (OR2 ) 2; - (CR'R") EOPO (OR') 2; 5 - (CR' R") qCOR2; - (CR"R") SO2R 3; - (CR R') 4 OSO3R2; - (CR' R") R24 - (CR' R") (R21; or - (CR"R") qR2 . R2: H; CF3; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; -(CR"R'")qOR20 10 - (CR' R") qSR2 ; - (CR"'R") qNR'R"; - (CR R") QOCONR R"; - (CR'R'") OCOOR2; - (CR'8R') NR4COOR'; - (CR R"9) NR4COR2 - (CR R") qNR'CONR 4 R ; - (CR2R) qNR 4 SO R'; - (CR'R") ,NR'SO NR'R"; - (CR' R") qCOOR'; - (CR'8R") qCONR4R"; - (CR"'R") qSO2NR4R"; - (CR'9R") PO (OR) 2; - (CR'"R'") 4 COR ; - (CR'R"R)qSO2R ; - (CR'R") R 24; 15 - (CR'R") R ; or - (CR'R") qR . R3: H; CF3; alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl. 20 R4: H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or a suitable N protecting group. R , R and R9 are independently defined as: H; F; CF3; 25 alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR'R') OR ; - (CR'R") SR2; - (CR'2R") NR'R"; - (CR'R K) OCONR4R"; - (CR"'R") OCOOR'; -(CR R") NRCOOR '; -(CR1'R") NR4COR', - (CR"R") sNR4CONR
T
R"; - (CR' R") NR4SO2R ; - (CRR") NR4SONR4R'; - (CR"R") ,COOR'; 30 - (CR'R" ) qCONR4R"; - (CR R") qSO2NR 4R"; -(CR'R") qPO (OR') - (CR' R") qCOR ; - (CR' R") SO2R2 ; - (CR"R') ,R24; - (CR' R") R2 ; or - (CR R") qR . R6, R8 and RM are independently defined as: H; F; CF3; 35 alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; or heteroarylalkyl.
WO 2011/015241 PCT/EP2009/060168 13 R": H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable protecting group; - (CRR9) rOR2 ; - (CRR 9 )rSR21 ; - (CR1R1),NR R ; 5 - (CR 1 R") rOCONR 4 R"; - (CR"R 9 ) rOCOOR'; - (CR"R") rNR4COOR"; - (CR") rNR'CONRR"; - (CR"R") rNRSO2R; "R")NRSO4R - (CR"R") qCOOR"; - (CR"R") qCONR 4 R"; - (CR"R") qCOR"; - (CR"R") qSO2R'; - (CR"R") qSO2NR R; - (CRIR) qR2 4 ; - (CRieR 1 9 ) R"; or -(CRR"l) R. 10 R" and R" are independently defined as H; or alkyl.
R
4 and R" are independently defined as: H; F; CF3; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; 15 arylalkyl; heteroarylalkyl; -(CRR") 0R"; -(CR"R") 5 NR'R" ; -(CR"R")sNR4COOR"; - (CR"R") SNR4COR ; - (CR"R") 5 NR4CONR4R"; - (CR"R") 5 NR4SO2R"; - (CR"R1) JNR'SO2NR4RI; - (CR"R") qCOOR"; - (CR"R") CONRIR"I; - (CR"R") qSONR4R"; - (CR'R") qCOR" . 20 R'1 and R" are independently defined as: H; F; CF3; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; or heteroarylalkyl. 25 Substituents introduced in the sub-definitions of the radical F2R Rare: R1: H; F; CF3; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 30 - (CR"0R") sOR"; - (CR2R" ) sSR"; - (CR"R"0) NR"R"; - (CR"R") OCONR"R"; - (CR"R") OCOOR"; - (CR"R") 9 NR'COOR"; - (CRR) sNR"COR" ; -(CR"R" ) 3
NR"CONR
0 R"; -(CR"R" ) 5
NR
0 SO2R 0 ; - (CR"R") sNR"SONR"R"; - (CR"R") gCOOR"; - (CR"R") gCONRR; - (CR2R") ,SO 2 NRR29; - (CR"R") qPO (OR 21 ) 2; - (CR"R"U) qCOR; 35 - (CR9R") 1SOR" ; - (CR9R3 )R"; - (CR"R")qR"; or - (CR"R)R".
WO 2011/015241 PCT/EP2009/060168 14
R'
9 : H; CE 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl.
R
20 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; 5 aryl; heteroaryl; arylalkyl; heteroarylalkyl;
-(CR
29 )R3U rOR ; - (CR2 9 R3 ) rSR 1 ; -(CR2 9
R
30
)NR
2
R
31 ; - (CRR 2 9 K ) rOCONR R'; - (CR 2
K
0 ) rNR 2 COOR'; - (CR-R 30 ) -NR 2
COR
3 -; - 2 CRR) rNR21CONR R; - (CR-K )R NR-SO 0 2R- ;-(CR2R") r NRSO 2 NR R - (CR 2 9 R3) qCOOR 2 1 ; - (CR 2
'R
30 ) qCONR 2
R
31 ; - (CR 29
R
3 ) qSONR 2 R; 10 - (CR 2
R
9 ) qCOR, - (CR0 3 2) SO 2 ; - (CR 2 9 K') 9
R
24 ; - (CR R 0 ) qK 2 ; or - (CR 2 9
K
0 ) qR 2 .
R
21 : alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or a suitable 0 15 protecting group.
R
22 : alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 29
R
3 D ) OR3 1 ; - (CR-R 3 0) SR3 1 ; - (CR 9
R
30 ) NR 2 8R; 31 20 - (CR 9
R
0 ) OCONR 3 R; - (CR 2
R
3 ) 9
NR
2
COOK
2 1; - (CR 9 R ) NKR"CORK - (CRR 29 R3D) NR 2 8 CONR 2 8R 3; - (CR 2 R3 0 ) 0 NR2 3
SOR
2 ; - (CR 29 R3 0 ) 3
NR"SO
2
NR
2 8R 3; - (CRR" 29 ) 5
COOR
2 ; - (CR"RR2) CONRR 2 3 1 ; - (CK 29
R
3 ) 9 SO2NR 2
R
91 ; - (CR 2 R) COR 3 ; -(CRR ) SO2R 2 ; -(CR"R 3 ) R 24 ; -(CRR 29 R) tR 2; or 20 30 23 - (CRK )tR 25
R
2 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 2
R
3 3 ) R 24 . R24: aryl, preferably an optionally substituted phenyl 30 group of type C6H 2
R
34 R R ; or a heteroaryl group, preferably one of the groups of formulae Hl-H34 (Table 4). Table 4: Groups of Formulae Hl-H34 WO 2011/015241 PCT/EP2009/060168 15 D3 R3 /NR 34 R4 Hl H2 H3 H4 N -N N-N p3 C~R36 R 6Xl R 36I Y y N H5 H6 H7 H8 34 N N3 N N N ~N R 3 H9 H10 Hll H12 N(--,R34 N 36 N' N p34 N R 36 -N N, N -- N H13 H14 H15 H16 N, NR 34R 34 N \/ N R 36 N LR 36 -Y H17 H18 H19 H20 H21 H22 H23 H24 NN. N N-) .N H25 H26 H27 H28 R36 4 NN
N-
3 N 4
N
WO 2011/015241 PCT/EP2009/060168 16 H29 H30 H31 H32 R4
R
3 4 N... 34 NN R38 H33 H34 R2: One of the groups of formulae H35-H41 as shown in Table 5 below. 5 Table 5: Radicals of formulae H35-H41
R
38
R
38
R
38
R
38
R
37 37 1 R37 ' 37 H35 H36 H37 H38 R34 R34 R34 R6 N R 35 N RR N 35 37IR 37 ' 37 R H39 H40 H41
R
26 : One of the groups of formulae H42-H50 as shown in Table 6 below. 10 Table 6: Groups of Formulae H42-H50 R38 R 38
R
38
R
38 N N N0N
R
37 %II H47 437 H 37 R37 H42 H43 H44 H45 WO 2011/015241 PCT/EP2009/060168 17 8 4 R34 N N R 38 L R 35 - -R3
R
3 8
R
34 R355 R37R R3 H50 R2 7 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable protecting group; or - (CRR 3 ) 4 R. 5
R
2 3 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable N protecting group; -(CR 32
R
33 ).OR2 1 ; - (CRR 3 ) NJR 3 R ; - (CRRO) sNR CONR 3 R ; 10 - (CR R) SNR COR; - (CRR") ,NR SO2NR; - (CR3 3 R 4) 3COOR2 1 ; - (CR 3 2R) qCOR 2; - (CR 3
'R
33 ) qSO2R' . R 2 : H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 15 - (CRR 32 33 ) 3OR 1 ; - (CRR 33 ) 3SR 1 ; - (CRR 33 ) NRR 31 ; - (CR 32
R
33 ) sOCONR2'R" 1 ; - (CR 2
R
33 ) sOCOOR 1 ; - (CR12R" 3 ) 'NR 3 COOR 21 ; - (CR 3 2R 33 ) NR 8 COR 31 ; - (CR 3 2R 33 ) -NR 2 CONR 2
R
31 ; - (CR 3
R
33 ) NR2 SOR 2; - (CR 32 R") NR 3 2 S02NR2'R" 1 ; - (CR1 3 R") gCOOR 1 ; - (CR1 2 R") GCONR28R 3 2; - (CR 32
R
33 ) qSO 3 NR2 3
R
3 ; - (CR 3 2R 33 ) 3 PO (OR 21 ) 2; - (CR 32
R
33 ) COR; 31 20 - (CR R") 'SO 2 R 2 ; - (CR R ) qR 3 '
R
30 : H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl.
WO 2011/015241 PCT/EP2009/060168 18
R
31 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or one of the groups of formulae H51-H55 as shown in Table 7 below. 5 Table 7: Groups of Formulae H51-H55 R39 R39 OR21 R39 I ~I I I ---[ C R 4 1 ---- C----- R 41 40 40 40 40 0-20 q U H51 H52 R39] NR28R43 R 39
R
39
R
12
R
39 11111 I S 1I --- C--C-- C- 1 -- C -C=C-- C R41 IR40 RR 4 0 q R40- R13[ R40 u u H53 H54 R39 R39 ----C -- Q- C-R41 I I I -R40 - R 40 H55
R
32 and R 33 are independently defined as H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl. 10
R
34 and R 3 5 are independently defined as H; F; Cl; CF 3 ;
OCF
3 ; OCHF2; NO 2 ; CN; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR2 9
R
31 ) OR 3 1 ; - (CR R 3 0 ) SR 3 1 ; - (CR9R 3 0 ) qNR 2 R ; 3 1 15 - (CR29R 33 ) gOCONR2R1 ; - (CR9R 3 0 ) qNR2 8
COOR
2 1 ; - (CR 9
R
3 1 ) NR28CORO 1 ; - (CR 9
R
30 ) qNR2 8 CONR28R ; - (CR29R 3 0) gNR2 3
SO
2 R2 3 ; - (CR29R" 3 ) QNR 3 2SO 2
NR
2
'R
31 ; - (CR"9R 3 0) gCOOR2 1
;
WO 2011/015241 PCT/EP2009/060168 19 - (CR2 0
R
3 ) qCONR R"; - (CR"R 3 0 ) S 0 2NRR 31 ; - (CR2 3
R
3 0 ) qCOR 31 ; - (CR R3' ) SOR ; or - (CR R ) 4
R
3 .
R
36 : H; alkyl; alkenyl; alkynyl; cycloalkyl; 5 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or -NR R 31 . R7: H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable 10 N-protecting group; - (CR29R 3 ) rOR 31 ; - (CRR 3 ) rSR ; -(CR R 3 ) rNR R ; -(CR 9R) rOCONR"; - (CR 0 R3) HNR2COOR21; - (CRR' ) NR2COR1; - (CR2'R0 ) NR2CONR2R3; - 2(CR9R) HRSR; -(CR2R8 ) HNR SOH2R R; - (CR"R31 )qCOOR; - (CR R) ) 4 CONR R; - (CR R' ) rSONR R; - (CRR' ) qCOR"; 15 - (CR 0 R) qSOR2; or - (CR "R )qR. R3: H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; -(CR'R3 )qOR"; - (CR2 0 R' )qSR' ; - (CR2R3 ) qNR R3 ; 20 - (CR2 0 R' ) ,NR COOR'1; - (CR'R3 ) 4 NR COR1; - (CR2'R' ) qHRCONRR ;' - (CR R3D) qCOOR'; - (CR"'R3 ) qCONR R"; - (CR'R3 ) COR3; or - (CR R') ,R" . R9: H; F; CF3; alkyl; alkenyl; cycloalkyl; 25 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 3 3R") 2OR; - (CR2 R") 2R 43; - (CR' R") 'COOR ; or - (CR' R 00 ) CONR2R4 . R40: H; F; CF; alkyl; alkenyl; cycloalkyl; 30 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR3R ) OR ; - (CR R") JNR R ; - (CR R3 ) COOR'; or - (CR R) 'CONRR 4 R4 1 : H; CF,; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; 35 aryl; heteroaryl; arylalkyl; heteroarylalkyl; -OR2'; -NR R43 -NR COR ; -NR COLOR ; WO 2011/015241 PCT/EP2009/060168 20 -NR SO R ; -NR2CONR8R" 3 ; -COOR; -CONR28R 3 ; -C(=NR)NR N3; -NR2 C(=NR")NR 28N; or one of the groups of formulae H56-H1lO as shown in Table 8 below. 5 Table 8: Groups of Formulae H56-H110 R 44 R 4 R 44 R 44 -- R45 -- N - N
R
46
R
4 5
R
4 5 R45 H56 H57 H58 H59 __ R ~NR 44 -- NR NR44 R44 R44 R 44 --- N ---- -- N N N N H60 H65 H62 H63 R 44 R 44 R R 44 N: N -- --- - / \ N N-N N-N N-N H64 H65 H66 H67 R44 R44 R 44 Q N N Q H68 H69 H70 H75 N R N4 o- N N R N H72 H73 H74 H75 R4R44N,-NNN Q Q H176 H77 H178 1179 WO 2011/015241 PCT/EP2009/060168 21 R44 RR44 /tT T N N--- N~N H80 H81 H82 H83 T R4545 45 N :i --- J / 45 / N --- ~R4 jN4 44 R 4N R 4N R H84 H85 H86 H87. T 44 4:444 R R R T N\//
-T--
H92 H89 H94 H91 R{J 4
T
1
~R
4 T - 4 4 T--\ T R TR
NR
4 TT T R044 R R 4 7' H92 H93H94 H9 WO 2011/015241 PCT/EP2009/060168 22 H100 H101 H102 H103 R44 R44 R 5 0 T T- -\\T H H5 H RH 0-2 0 R 49 H
R
49 0-2
R
49 H104 H105 H106 H106 R4 __ -49 __L -R49 (n H108 H109 H110
R
42 : H; alkyl; alkenyl; cycloalkyl; cycloheteroalkyl; aryl; heteroaryl; (CR 23 R) OR 21 ; - (CR 2 3 R) 2NR 8
R
43 ; - (CR 2
R
3 ) qCOOR 2 ; or 5 - (CR 23
R
3 3 ) qCONR 21
R
43 .
R
43 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or a suitable N protecting group. 10 R44, R45 and R46 are independently defined as H; F; CF 3 ;
OCF
3 ; OCHF 2 ; NO 2 ; CN; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl;
-OR
2 ; -NR 2
SR
4 ; -NR2 8
COR
23 ; -NR 28
SOR
2 3 ; -NR 28 CONR2'R 43 ; -COR13; 15 -SO2R 23 ;
R
47 : H; CF 3 ; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl;
-COOR
2 ; or -CONR"R". 20
R
4 8: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; cycloheteroalkyl; aryl; heteroaryl; WO 2011/015241 PCT/EP2009/060168 23 - (CRRt) tO1; - (CR3 ) tNR 28
K
4 R; - (CRR"K3) tCOOR21; - (CR"R") R CONR 2 R 43 R49 and R' are independently defined as H; F; CF3; alkyl; 5 alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 32
R
33 ) OR ; -(CR2R ) KNR 8
R
4 ; - (CR R")qCOOR"; or - (CR'R")qCONR R". Taken together the following pairs of said substituents 10 can define cyclic structural elements: Taken together (R 4 and R); (K4 and R); (R and K'); (R and R') ; (R and R9); (K 8 and R"); (R and R) ; (R' and R) ; (R and RK) ; (R' and R') ; (R9 and R") ; (R" and R') ; (R" and R) ; (R 8 and K"); (R and R 2); (R' and ")4; (R' and R 4 ); (K" and R); 15 (K" and K") ; (K' 4 and ") ; (R and R') ; (R' and K") ; (R' and
R
4 ; (R" and K"); (K 4 ' and R"); (K4 4 and K 4 8); or (R 44 and R46) can form optionally substituted cycloalkyl or heterocycloalkyl moieties. In addition, the structural elements -NR4R; -N R ; -NR R or 20 -NR 8 R43 can form one of the groups of formulae Hl1l-H118 as shown in Table 9 below. Table 9: Heterocyclic Groups Defined by Linking the Residues of the Disubstituted Amino Groups -NR 4R; -NRR ; -NR 2R or 25 -NRPK. R4 R 50 R5o R 49 R 39 /-\ R 39 T/- -\\ T -- N -- N - -N Q - R 39 sR u49 H R 50 H H111 H112 H113 H114 WO 2011/015241 PCT/EP2009/060168 24 R44 R 49
R
5 M T ,R44 H R 49 A\ '\<__N N T H H H --- N Q tR -- NH R49 t R49 R5o R 50 H115 H116 H117 H118 Variable heteroatoms and connector groups in the aforementioned structures are Z: 0; S; S(=0); S(=O) 2 ; or NR 8 . 5 Y: 0; S; or NR 37 . X: 0; S; S(=0); or S(=0)2. Q: 0; S; or NR 2 . U, V and W: As defined in Table 3. T: CR or N. In case T occurs several times in the same 10 ring structure each I is defined independently of the other. And indices are defined as: q=0-4; r=2-4; s=1-4; t=0-2; and u=1-2. Salts are especially the pharmaceutically acceptable salts of 15 compounds of formula I. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of type I with a basic nitrogen atom, especially the 20 pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, 25 decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, WO 2011/015241 PCT/EP2009/060168 25 cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2 5 disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4 methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic 10 protonic acids, such as ascorbic acid. As used in this description, the term "alkyl", taken alone or in combinations (i.a. as part of another group, such as "arylalkyl") designates saturated, straight-chain or branched 15 hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms. In accordance with a preferred embodiment of the present invention "alkyl" is "lower alkyl" which designated alkyl groups having up to 6 carbon atoms. 20 The term "alkenyl", taken alone or in combinations, designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties can exist as E or Z configurations, 25 both of which are part of the invention. The term "alkynyl", taken alone or in combinations, refers to an aliphatic hydrocarbon chain and includes, but is not 30 limited to, straight and branched chains having 2 to 10 carbon atoms (unless explicitly specified otherwise) and containing at least one triple bond. The term "cycloalkyl", taken alone or in combinations, refers 35 to a saturated alicyclic moiety having from three to ten carbon atoms.
WO 2011/015241 PCT/EP2009/060168 26 The term "heterocycloalkyl", taken alone or in combinations, describes a saturated or partially unsaturated heterocyclic moiety having from three to seven ring carbon atoms and one or 5 more ring heteroatoms selected from nitrogen, oxygen and sulphur. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The term "aryl", taken alone or in combinations, designates 10 aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF 3 ,
NO
2 , lower alkyl or lower alkenyl. 15 The term "heteroaryl", taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of 0, S and N and whereby the heteroaryl radicals or 20 tautomeric forms thereof may be attached via any suitable atom. Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for "aryl". The term "arylalkyl", as used herein, whether used alone or as 25 part of another group, refers to the group -Ra-Rb, where Ra is an alkyl group as defined above, substituted by R 2 , an aryl group, as defined above. Examples of arylalkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. Similarly, the 30 term "lower arylalkyl", refers to the above moiety -Ra-R but wherein Ra is a "lower alkyl" group. The term "heteroarylalkyl", whether used alone or as part of another group, refers to the group -Ra-R', where Ra is an alkyl 35 group as defined above, substituted by R, a heteroaryl group, WO 2011/015241 PCT/EP2009/060168 27 as defined above. Analogously the term "lower heteroarylalkyl", refers to the above moiety -Ra-Rc but wherein Ra is a "lower alkyl" group. 5 The terms "alkoxy" and "aryloxy', taken alone or in combinations, refer to the group -O-R', wherein Ra, is an alkyl group or an aryl group as defined above. "Amino" designates primary (i.e. -NH,), secondary (i.e. -NRH) 10 and tertiary (i.e. -NRR') amines. Particular secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, arylalkylamines and diarylamines wherein the alkyl is as herein defined and optionally substituted. 15 The term "optionally substituted" is intended to mean that a group, such as but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxy and aryloxy may be substituted with one or more substituents independently selected from, e.g., halogen (F, Cl, Br, I), 20 cyano (-CN) , nitro (-NO) , -SR , -S (0) R , -S (0) 0 R", Ri, -C(0)Ra,- C() OR, -C (0)NRR , -C (=NRa) NRb,, -OR-, OC (0) Ra, -OC (0) ORa, -OC (0) NRbRE, -OS (0) Ra, -OS (0) 2Ra, -OS (0) NRbRO, -OS(O)NRR", -NRRe, -NRaC (0) R, -NRaC (O) OR-, -NRaC (0) NRbR, -NRa bpc,~ ~ ~ aS b S()2b C(=NR') NRR\, -NRS(0)R, -NRaS()R wherein R, R, R, and Rd 25 are each independently, e.g., hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl as described herein; or R" and Rc may be taken together with the N atom to which they are attached forming heterocycloalkyl or heteroaryl. These groups in turn can be substituted with any described 30 moiety, including, but not limited to, one or more moieties selected from the group consisting of halogen (fluoro, chloro, bromo, or iodo), hydroxyl, amino, alkylamino (e.g., monoalkylamino, dialkylamino, or trialkylamino), arylamino (e.g., monoarylamino, diarylamino, or triarylamino), hydroxy, WO 2011/015241 PCT/EP2009/060168 28 carboxy, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. Said groups, especially but not limited to hydroxy, amino and 5 carboxyl, may be either unprotected or protected, if necessary, as well-known to those skilled in the art. Examples of suitable protecting groups are as detailed in Peter G. M. Wuts, Theodora W. Greene, Greene's Protective Groups in Organic Synthesis, John Wiley and Sons, 4th Edition, 2006. 10 As used herein, all groups that can be substituted in one embodiment are indicated to be "optionally substituted," unless otherwise specified. 15 As mentioned earlier herin, the term "lower" designates radicals and compounds having up to 6 carbon atoms. Thus, for example, the term "lower alkyl" designates saturated, straight chain, or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, a 20 butyl, isobutyl, t-butyl, and the like. Similarly, the term "lower cycloalkyl" designates saturated cyclic hydrocarbon radicals having up to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. 25 The present invention includes within its scope so-called "prodrugs" of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds, which in vivo are readily convertible into the required compound. Conventional procedures for the selection and preparation of 30 suitable prodrug derivatives are described, for example, in Hans Bundgaard, Design of Prodrugs, Elsevier, 1985; and in Valentino J. Stella et al., Prodrugs: Challenges and Rewards, Springer, 1st ed., 2007.
WO 2011/015241 PCT/EP2009/060168 29 Some of the aforementioned substituents can occur several times within the same molecular entity, for example, but not limited 14 15 16 17 18 29 28 29 30 31 32 - 39 40 to R", R , R", R , R , R", R , R , R , R , R> R 0 , R , R '1 4' 43 4 05 '16 5 R , R , R , R , R , R , and R. Each of such multiply 5 occurring substituents shall be selected independently from the other radicals of the same type and within the scope of the definition of the respective group. All possible stereoisomers, explicitly also including rotamers 10 and atropisomers, of macrocycles of type I are part of this invention. The general scope of the current invention is defined by groups of selected building blocks A, B and C and the appending 15 substituents as outlined in this section. Building blocks Al-A626 (Table 10) constitute a subset of possible building blocks based on the ring systems al-a25 (Table 1). As structural characteristic, groups of type A carry 20 one nucleophilic moiety XH (where X is 0 or S) and one carboxylic acid C(O)OH functionality. The underlying divalent radicals of type -X-a-CO- are an integral part of macrocyclic backbones of type I, into which they are incorporated by appropriate reactions of the XH and COOH groups of the 25 respective starting materials with suitable reactants. As mentioned earlier hereinabove, building blocks of type A act as templates and exert an important conformational constraint on products of type I. The structural effects of building 30 blocks of type A depend largely on the relative orientation of the attachment vectors of -X- and -C(O)- and on the spatial distance between these groups. Molecular modeling revealed that the distances (typically between 2.5 and 7.5 A) and vector arrangements for -X- and -C(O)- in Al-A626 (Table 10) vary WO 2011/015241 PCT/EP2009/060168 30 considerably, thus strongly influencing the conformations of macrocycles of type I. 5 The general scope of the current invention is defined by groups of selected building blocks A, B and C and the appending substituents as outlined in this section. Building blocks A1-A626 (Table 10) constitute a subset of 10 possible building blocks based on the ring systems al-a25 (Table 1). As structural characteristic, groups of type A carry one nucleophilic moiety XH (where X is 0 or S) and one carboxylic acid C(O)OH functionality. The underlying divalent radicals of type -X-a-CO- are an integral part of macrocyclic 15 backbones of type I, into which they are incorporated by appropriate reactions of the XH and COOH with suitable reactants. As mentioned earlier hereiabove, building blocks of type A act as templates and exert an important conformational constraint 20 on products of type I. The structural effects of building blocks of type A depends largely on the relative orientation of the attachment vectors of -X- and -C(0)- and on the spatial distance between these groups. Molecular modeling revealed that the distances (typically between 2.5 and 7.5 A) and vector 25 arrangements for -X- and -C(0)- in Al-A626 (Table 10) vary considerably, thus strongly influencing the conformations of macrocycles of type I. Table 10: Radicals A1(al)-A626(a25) R1R1 R1 R1 X, X, / - X, 0 1 Al(al) A2(al) A3(al) A4(al) WO 2011/015241 PCT/EP2009/060168 31 01 ~ R 1 R o 'N x a0 1 0& RI x I x R I " II II A9 (al1) A10O(al) Alli(al) A12 (al) IR4
R
1 I R R 3 4 R R 34 Rl-~~~ ~ ~ 'X 4 X , 0- 0 A13 (al) A14 (al) A15 (al) A16 (al)
R
3 4 ~.34 R 34N , R34 X, 00 A17 (al) A18 (al) A19 (al) A20 Cal)
RR
3 X, 1 0: 0 X A21 Cal) A22 (al) A23 Cal) A24 Cal) NR 34 00 R 3 4 0 R3 4 0 R1 RiN x RN x
R
34
I
WO 2011/015241 PCT/EP2009/060168 32 A25 (al) A26 (al) A27 (al) A28 (al) 3R3R34 R 35 R 1 3R 35 l X" Xl X" R- R 34 ~X, 00 A29 (al) A30 (al) A31 (al) A32 (al) Rl ~R 35 R R 34 R3 5R lR3
R
34 - 0 0 A33 (al) A34 (al) A35 (al) A36 (al) Rl 35 R 35 R 35
R
34
R
35 R l R 34 R X"- R 34 " R R 34 ' , X, 0 " 0 0~ A37 (al) A38 (al) A39 (al) A40 (al) R 3 4 R R 35 R3 R 35
RR
3 3 RR 0 '. 0:1N: x 0: ~ 0 5 0 x I R5 A41 (al) A42 (al) A43 (al) A44 (al) r-3 5R34R 35 0 R34 0
-
-R
35 R 35
X
5 R1 X R1q X 51 1 x RR 34 A45 Cal) A46 (al) A47 Cal) A48 Cal) WO 2011/015241 PCT/EP2009/060168 33 o R 34 0 R 34 0 0 R 34 - t::,k, R34 R. 35 R1 R X R3 x N)x A49 (al) A50 (al) A51 (al) A52 (al)
R
35
R
35 RIR5 3 52 1 52
P
35
P
52 35 R 4P 34 x' R 4 R A53 (al) A54 (al) A55 (al) A56 (al) 35R5P0 R4R 3 5 0 R 34 N o x R1 X R2~ x A57 (al) A58 (al) A59 (al) A60 (a2) N -SN R 1 N N x A61 (a2) A62 (a2) A63 (a2) A64 (a2) Ni" 0 ~ 00 A65 (a2) A6 6(a2) A67 (a2) A68 (a2) P 1 R N II P 1 N R 1 R n- X", X" N X 0 0 A69 (a2) A7 0(a2) A71 (a2) A72 (a2) WO 2011/015241 PCT/EP2009/060168 34 R' N y R x x ' 'z' INl X ', X A7 3(a2) A74 (a2) A7 5(a2) A7 6(a2) NR N R wN 0 0 IN X 0 -~x 0 A77 (a2) A7 8(a2) A7 9(a2) A80 (a2) NN N 0~ 0 _zr0 K R51 R51 NR A81 (a2) A82 (a2) A83 (a2) A84 (a2) 0 0 0 0 ,I I N' A85 (a2) A8 6(a2) A87 (a2) A88 (a2) 0 R 36 N R 34
R
3 6 N 'rN RN -R N x l Xl X, Ri X" Ri 0 0~ A89 (a2) A9 0(a2) A91 (a2) A92 (a2) N R 36
R
34 N R3N NR3 A93 (a2) A94 (a2) A95 (a2) A96 (a2) WO 2011/015241 PCT/EP2009/060168 35 l R 36 R' N R 1 N R 36 R X" R4 X X" R 36 'X, A97 (a2) A9 8(a2) A99 (a2) AIO00(a2) R 36 R iR Rl NR 3 6 N 36 X"N " N X R 36 X" 000' 0' AIO I(a2) A102 (a2) A103 (a2) A104 (a2) N R j N - 3 "N I X" R R 36 X - X" -x" 0" 0" 0 " A105 (a2) A106 (a2) A107 (a2) A108 (a2) R 34 R R 36 NR Rl~ N- R
R
6 N R R 1 N6 R, R 3 34 0 '- 0 NX 0 A109 (a2) A110 (a2) AM15(a2) A112 (a2) R 36
R
1 lR 0:N N 34 R3 R 34 0 0 N 0 W XN X N X WO 2011/015241 PCT/EP2009/060168 36 A117 (a2) A118 (a2) A119 (a2) A120 (a2) R 3 4 "'N RN3 R 3 6 N R 1 n3 0N R N 11 0 N"0 0 N-1 X 1-rN" A1251(a2) A1226(a2) A123 (a2) A1248(a2) R 3 6 R36 3 4 06
NR
3 Rl 4N 0; N 0: N R 1 R"5 A1259(a2) A1260(a2) A127 (a2) A12(a2) 0N R 36 R R3 0 R 3 N NN 3 -- 0N -, 'N X1 51 R X R 1 NX A1293(a2) A1304(a2) Al15(a2) A132 (a2) 0 0 R 3 6 0 0 R3 R 36 R 3 A133 (a2) A1348(a2) A1359(a2) A1360(a2) 0 0 R 40 0 3 N R 3 6 N N 36 N) I XR X 0 0 00R36 WO 2011/015241 PCT/EP2009/060168 37 A141 (a2) A142 (a2) A143 (a2) A144 (a3) ,N RI NZ, R 1 N..l N 'N XR X" X" N- X" 0 0 0x A145 (a3) A146 (a3) A147 (a3) A148 (a3) NN. l N NN Rl N X'',- 0 N) 0 x x x A149 (a3) A150 (a3) A151 (a3) A152 (a3) _N-N 0 R 1 0 RAN
R
34 N N R1'N X zNlX A153 (a3) A154 (a3) A155 (a3) A156 (a3) ,N RI R 34 NZ, R 1 N R 3 N A157 (a3) A158 (a3) A159 (a3) A160 (a3)
R
34 0 R 1 0 R 34 - R 34 N- N N.0 XN XN XR5 0~ A161 (a3) A162 (a3) A163 (a3) A164 (a3) N.. RN 0 -" K ,N N 'NX 0 N...~" -.. x0 WO 2011/015241 PCT/EP2009/060168 38 A165 (a3) A166 (a4) A167 (a4) A168 (a4) N N X I I--
N
A169 (a4) A170 (a4) A171 (a4) A172 (a4) N~ 0l N X 0, N A173 (a4) A174 (a4) A175 (a4) A176 (a4) 0 RI N R 36
R
36 N R 1 3 N- NN N N N N, -- NI X " Il0 ' 0 0 , A177 (a4) A178 (a4) A179 (a4) A180 (a4) RI
R
36 R N )1- N R 34 -~N R34
R
36 X" 0 NX 0 N XN A1:(4 0 - N)X A8(a)A182 (a4) A183 (a4) A184 (a4)
R
36
R
36 0 R34 0 Rl 1 1 11,- UN R 36 N I N N-N I
NC
I R5 R A185 (a4) A186 (a4) A187 (a4) A188 (a4) WO 2011/015241 PCT/EP2009/060168 39 N " 0 0 x, N lX 0" N IX 0 0 I A189 (a5) A190 (a5) A191 (a5) A192 (a5) 0 0 R 34 R N I
R
1 N X N X X, X, A193 (a5) A194 (a5) A195 (a5) A196 (a5)
R
1 N>R 34 R 3 4 N R 1 0 34 0 0, N X -N :( NX 3 I lR N X R34N X A197 (a5) A198 (a5) A199 (a5) A200 (a5) Rl N R R 1 N ~ N "r, N N ""1N 'NN X, Nj- " N X N 1X 0 0 A201 (a6) A2 02 (a6) A203 (a6) A204 (a6) 0 p 1 0 yR '-'N -Ri "' x x N~-N xN X 'N XII 0 A205 (a6) A2 06 (a6) A207 (a7) A208 (a7) 0 " 0 0"' A209 (a7) A2 10 (a7) A2112(a7) A212 (a7) WO 2011/015241 PCT/EP2009/060168 40
R
1 R R 1 y 0 \ o 0\ 0 x y x y x I 1111 R 5 1 A213 (a7) A214 (a7) A215 (a7) A216 (a7) 0 x- 0, 7 x" R34~ 0 0 A21(a7) A2218(a7) A2193(a7) A2204(a7)
R
1
R
34
R
34
R
1
R
3 4
R
34 Y Y A221 (a7) A2226(a7) A223 (a7) A2248(a7) Y Yx R 1 "'- x A233 (a7) A234 (a7) A235 (a7) A228 (a7) WO 2011/015241 PCT/EP2009/060168 41 y RiN-Y Y-N 0 .
0 A237 (a9) A238 (a9) A239 (a9) A240 (alO)
R
1
R
1 R y 0i 0 00 A241 (alO) A242 (alo) A243 (alO) A244 (alO) -- Ri/Iy 0 00 0 A245 (alO) A246 (alo) A247 (alO) A248 (alO) A249 (alO) A250 (alO) A251 (alO) A252 (alO) X" X" X"-- R 1 X, 0 00 A253 (alO) A254 (alO) A255 (alO) A256 (alO) WO 2011/015241 PCT/EP2009/060168 42 YY 0 0 1 A2571(alO) A258 (alO) A2593(alO) A2604(alO) RNyR y X, X, X A2615(alO) A2626(alO) A2637(alO) A2648(alO) Y\ R 1 N x 00 A269 (alO) A270 (alO) A271 (alO) A272 (alO) 0N5a :;p 0,: 0 .'I A273 (alO) A274 (alO) A275 (alO) A276 (alO) WO 2011/015241 PCT/EP2009/060168 43 0 Y I x A277 (alO) A278 (aiC) A279 Calb) A280 (alC)
R
1 Il y o N x R5 A281 (alO) A282 (alC) A283 (alO) A284 (alO) RI 0 N 0 0 RIR o xR 0: 0N 0 x 0 I I A280 (alO) A290 (alC) A291 (alO) A292 (alO) Rl y y0 / -l 0 'N0 RN 1/ ' I R5 A293 (alO) A294 (alC) A295 (alO) A296 (alO) WO 2011/015241 PCT/EP2009/060168 44 - - 0Rl R - 00 Y \R I I A297 (alO) A298 (alo) A299 (alO) A300 (alO) 0 it~ ~ 0 Y 0 Y R 1 Xl 0 4 x A301 (alb) A302 (alO) A303 (alb) A3 04 Calb) 00 R3 6X 0 A305 Calb) A306 (alO) A307 Calb) A308 (alO) R 41R 34 R iR 34 'N X, X -l R - R 36 0 00 0 A309 Calb) A310 (alo) A311 Calb) A312 (alO) Y -, Y X, y X, o R 36
-
0 0 0 A313 (alO) A314 (alO) A315 (alO) A316 Calb) WO 2011/015241 PCT/EP2009/060168 45 Rl 34 Rl R4 RlR 34
R
36 o o 0 A317 (alO) A318 (alb) A319 (alO) A320 (alO) RlR4 RI 3 3 R l R 34 0 0 A321 (alO) A322 (alb) A323 (alO) A324 Calb) RI 34 ~ A325 (alO) A326 (alO0) A327 (alO) A328 (alO) -l RRi R34 y 3
R
34
RX,
0~ A329 (alO) A330 (alO) A331 (alb) A332 (alO) WO 2011/015241 PCT/EP2009/060168 46 Yl R - y 4 R R 3 4
-
\I" X" "X 00 A337 (alO) A338 (alO) A339 (alO) A340 (alO)
R
3 , R3 ,R 1 X" R34 yy A341 (alb) A342 (alO) A343 (alb) A344 Calb) 0 0 A345 (alO) A346 (al 0) A347 (abeD) A348 (abeD) RyR 3 6 \ R 3 6 \ \ K 0 0. X 0 0 0 Y 0 l R 04 N 0 y x, x A353 (abeD) A354 (abeD) A355 (abeD) A356 (abc) WO 2011/015241 PCT/EP2009/060168 47
R
34 N R R 0 N y R 37 -N X' N 37 -X R -N X R1 R 'N X 0 R1 ' O0 A357 (alO) A358 (al1) A359 (all) A360 (all) RI R1 R 1
R
37 N R37 R37--N / RN R N NN N N' X'' N X' X 0 0 O 'oO A361 (all) A362 (al1) A363 (all) A364 (all) R37 R1 R 3 N N R1 N R R 37R\N R N 1N N- 3 0 Ix X X'RX O0 A365 (all) A366 (all) A367 (all) A368 (all)
R
37 R37 R 37
R
1 R7 R N R RII ~\j N j NX 0N A369 (all) A370 (al1) A371 (all) A372 (all) RT R737 R1 R3R7 N R\ R\R 37 N N
R
1 NR1 N X X/ X R1 0 O '' O ''AO ' A373 (a12) A374 (a12) A375 (a12) A376 (a12) WO 2011/015241 PCT/EP2009/060168 48 R7R 37
R
1
R
1 N NN N ~N R 1 3 \K- X" ' : N X 0:K N X A377 (al2) A378 (a12) A379 (al2) A380 (al2) lR 37
R
37
R
1 R N N R7 -N
-
3 7 N N o K5 x A381 (al2) A382 (a12) A383 (al2) A384 (al2)
R
1 l -NkR -" -N
N\R
1 R 37 N __ I 3 ~ N I 0 X - R 37 N 37 0 0 0 A385 (al2) A386 (a13) A387 (al3) A388 (al3) R7R \N R\N \N \ N N \ R 0 N X 0 N X A389 (al3) A390 (a13) A391 (al3) A392 (al3) R 37 IR 37
R
1
R
37
R
37 Rl R 1 I NIR 0 0 N X 0 N IX 0 N IX A393 (al3) A394 (a13) A395 (al3) A396 (al3) WO 2011/015241 PCT/EP2009/060168 49
R
1 R 37
R
37 R 0 N/ N R 3 7-N -~N R 37 -N N 0 / Q 0 A397 (al3) A398 (a13) A399 (al4) A400 (al4) RI R37 R 1 R 37 3 N IN' N
R
3 7 -N N /l / -- N-. -N N 0 0 0 A401 (al4) A402 (a14) A403 (al4) A404 (al4)
%R%
7 R% R 3 N N~N ~N N X N X N X 0. 0 00 x A405 (al4) A406 (al4) A407 (a14) A408 (a14) - Rl ~R 3 7N R R R37-N : N N-R37 N-R 37 IN0 N NN 0 'N X 0 .- 0 A409 (aN4) A410 (a14) A411 (aN4) A412 (aN4)
NNN-R
37 N Rl N 'Rl R~ 51 A413 (aN4) A414 (a15) A415 (al5) A416 (al5) WO 2011/015241 PCT/EP2009/060168 50 RY N~ 0 A417 (al5) A418 (a15) A4 19 (al5) A420 (al5) Yl j- /- N R - \ R- X N )/ x" x l X 0 0" 0"0 A421 (al5) A422 (a15) A423 (al5) A424 (al5) Y ~ y Rl N R 1 l<\yR N x <YR X 'N , N N" 0 0" 0"0 A425 (al5) A426 (a15) A427 (al5) A428 (al5) N N N
R
1 X" .- " 0 X0:~~N A429 (a15) A430 (a15) A431 (a15) A432 (a15) 0 xN 0 N, 0 K I IR 5 1 X A433 (al5) A434 (a15) A435 (al5) A436 (al5) WO 2011/015241 PCT/EP2009/060168 51 Rl N N N
R
51 0 R 51 A437 (al5) A438 (a15) A439 (al5) A440 (al5) N NN 0 0 x 0 x A441 (al5) A442 (al5) A443 (al5) A444 (al5) N~ 0 - , xl I A445 (al5) A446 (a15) A447 (al5) A448 (al5) 0 RN" R y-N R5 .N/ y X" R X R5 3 4 R 53 , l 0~ 0 ' A449 (al5) A450 (al6) A451 (al6) A452 (al6) Rl y-N R53 N 3R 5 3 N-y R R 53 R Y N, N
R
1 X, A453 (al6) A454 (al6) A455 (al6) A456 (al6) WO 2011/015241 PCT/EP2009/060168 52 N y-N y R 53
R
5 3 :! / -4 0 0 0 A457 (al6) A458 (aiG) A459 (al6) A460 (al7) 0 0 A461 (al7) A462 (a17) A463 (al7) A464 (al7)
R
1 l , X "- X " x , 00"0 A465 (al7) A466 (a17) A467 (al7) A468 (al7)
R
1 R 0"0-0- 0" A469 (a17) A470 (al7) A471 (a17) A472 (a17) 'N RN RN 0" 0 0 0"0 A473 (al7) A474 (a17) A475 (al7) A476 (al7) WO 2011/015241 PCT/EP2009/060168 53 RN R 1 I 0 x ~ I 0 A477 (al7) A478 (a17) A479 (al7) A480 (al7) 0 ~ Oz I~ x 0 x 0 I I I IR 5 1 I A481 (al7) A482 (a17) A483 (al7) A484 (al7) 00 Nx A485 (al7) A486 (a17) A487 (al7) A488 (al7) -~0 R 1 0 Rl0 A489 (al7) A490 (a17) A491 (al7) A492 (al7) 0 0 oR 34 x N x R 51
-
A493 (al7) A494 (a17) A495 (al7) A496 (al7) WO 2011/015241 PCT/EP2009/060168 54
R
34 R 34 34D3 N.l 34 I3-l X 00 A497 (al7) A498 (a17) A499 (al7) A500 (al7) Rl RlRR3 x - 0 A501 (a17) A502 (a17) A503 (a17) A504 (a17) A505 (al7) A506 (a17) A507 (al7) A508 (al7)
R
1 l xx A509 (al7) A510 (a17) A511 (al7) A512 (alS) WO 2011/015241 PCT/EP2009/060168 55 N N N NN X" X" N1 N 1 A517 (al8) A518 (alB) A519 (al8) A520 (al8) X" NN ,- N. X, 0 0-0 0" A521 (al8) A522 (al8) A523 (a18) A524 (alS) R l ' N NN X, R X, 'N', 0" 0" 0 0" A525 (al8) A526 (alS) A527 (al8) A528 (al8) ''N' x N 0' A529 (al8) A530 (al8) A531 (aiB) A532 (aiB)
N
1 N NN 'N N Rl 0 ' N 7 0 ' x A533 (al8) A534 (alS) A535 (al8) A536 (al8) WO 2011/015241 PCT/EP2009/060168 56 N X - N XN Nl X 11 1 0 0' I A537 (al8) A538 (al8) A539 (al8) A540 (alS) N N N IN 0 I0 0 -0 N 0 I x A541 (al8) A542 (al8) A543 (al8) A544 (al8)
NR
1 0 ol 0o 1 - , N -- NR -- N 0o N x x'R A545 (a18) A546 (al8) A547 (a18) A548 (al8)
-
N N -N 0 0 0 0 A549 (al9) A550 (a19) A551 (al9) A552 (al9) 14 N- N N N 0 N xx 0 A553 (al9) A554 (a19) A555 (al9) A556 (al9) WO 2011/015241 PCT/EP2009/060168 57 N X 0 '-0 -N X N X N XI A557 (al9) A558 (a19) A559 (al9) A560 (al9)
-
N X X N X A561 (al9) A562 (al19) A563 (al9) A564 (al9) N - R, -l R 1 RyN tN N ."r N)O~N X NN.' N ' A 00 A565 (a2 0) A566 (a2 0) A567 (a20) A568 (a20) Rp 1 lR R' N N N Xi N N 0 N- X 0: 1' N -,X 00 N N-, '1 . 0 N N 0 ~ 0 A569 (a20) A570 (a20) A571 (a20) A572 (a20) WO 2011/015241 PCT/EP2009/060168 58 N IN N N NI T'I -- NN NN1 N", X x- X"N X A577 (a20) A578 (a2l) A579 (a2l) A580 (a2l) I N N N N T A581 (a21) A582 (a21) A583 (a2l) A584 (a2 1) YI R' N Rl yR_ N N - - 'N N N I X II A585 (a21) A5 86 (a2 1) A587 (a2 1) A588 (a22) N. N XN N l N 0 -, A589 (a22) A590 (a22) A591 (a22) A592 (a22) R'yRI R 1 N N R l I N N 't - rA~x NN. N I ~ N<X 0 5 -M o N X A593 (a22) A594 (a22) A595 (a22) A596 (a22) WO 2011/015241 PCT/EP2009/060168 59 NN-. N N NN N. N 0N 0 0..L N X N X 0 N XN X N X A597 (a22) A598 (a22) A599 (a22) A600 (a22) ~R' R' N RN R N NN N N ~NX N Np.. 0 -N 0, NXNX N I I 0 A601 (a22) A602 (a23) A603 (a2 3) A604 (a23) RlY N 1R R 1 N N R 1 N .- - . N N -. N 0 N 1,X N' X 0 N 1 X 0 N X A605 (a23) A606 (a23) A607 (a2 3) A608 (a2 3)
R
R
38 x, R 3 8 x R-' 0 .
38 0 0 0 A609 (a24) A610 (a24) A6 11 (a24) A612 (a24) Rl 0 0 Rl 0 0. R 38
R
38 f 3 A613 (a24) A614 (a24) A615 (a24) A616 (a24) WO 2011/015241 PCT/EP2009/060168 60 1R1 R'R |0 -- , O 3 x R 38 0 A617 (a24) A618 (a24) A619 (a25) A620 (a25) O R R 0 xx 0 A621 (a25) A622 (a25) A623 (a25) A624 (a25) oRo RP R R X-1X A625 (a25) A626 (a25) Divalent building blocks B1-B21 (Table 11, hereinbelow) constitute a subset of possible building blocks based on the ring systems b1-bl (Table 2, above). They are based on 5 optionally substituted cyclic secondary amines carrying a moiety of type -CHR3-LG, wherein LG is a suitable leaving group (e.g., but not limited to, -OH forming a suitable LG in situ during Mitsunobu reactions, or halogens like -Br or -I amenable to SN reactions) that can be replaced by the nucleophilic 10 groups of building blocks A thus forming an ether (-0-) or a thioether (-S-) linkage between building blocks of type A and B. In most products of type I, the secondary amine nitrogen of building block B forms a tertiary amide linkage with the carboxyl group of building blocks of type C. In case a suitable 15 exocyclic amine functionality is present, it can be, instead of the ring-nitrogen, involved in the formation of a secondary or WO 2011/015241 PCT/EP2009/060168 61 preferably tertiary amide bond to C. Such an alternative binding mode is realized with, but not limited to B10. By virtue of inducing peptidyl cis-trans isomerization or 5 stabilizing cis amide bonds, building blocks of type B can function as conformational modulators in products of type I. Table 11: Radicals B1-B21 R2 R2 3
RR
3 R2 3 N - RR B1(bl) B2(b2) B3(b2) B4(b3) R 2 R 2 R 3 N R R 2 RN # I I R3 ' R3 B5(b3) B6(b3) B7(b3) B8(b3) R 27 3 RN N R N 3 R3R N N B9(b3) B10(b3) B11(b4) B12 (b4) R2QR2 ,,2 R SNN'
R
3
R
3 N '3R(R 4 B13 (b4) B14 (b4) B15 (b4) B16 (b4) WO 2011/015241 PCT/EP2009/060168 62 N N N ' R 'I B17 (b5) B18 (b8) B19 (b1O) B20 (b1l) N ' R3 B21 (b1l) The divalent moiety C may consist of an ensemble of one to three subunits cl-c3, each derived from suitably protected and functionalized amine or amino acid derivatives. As a 5 consequence the C moiety directly influences the ring size of the resulting macrocycle and can be regarded as spacer or linker. This linker ensemble C is joined to building block A via its N-terminus and to building block B via its C-terminus to form a macrocyclic ring of type I. According to its 10 definition the connections within the linker ensemble, i.e. V or W, can be accomplished by amide bonds (-NR4-C (=O) -) , an alkene[1,2]diyl (-CHR 2 =CHR-) , an alkane[1,2]diyl (-CHR1 2
-CHR'
3 -) , or methylene-heteroatom moiety (-CHR 3 -Z-) , an oxalyl unit (-C(=O)-C(=O)-) or a disulfide bridge (-S-S-). With 15 respect to the macrocyclic backbone of I it follows that the linker C contributes at least one amide bonds. Suitable linker C can be represented by, but are not limited to, the moieties shown in Table 12. For example Cl represents a 20 linker moiety constituted of one to three a-amino acid derivatives connected along their main chains, while C7-C1O are equivalent to dipeptide moieties of $- amino acids. Te simplest embodiments in which at least one connection between the subunits is realized by a non-amidic group are C2-C5. Finally WO 2011/015241 PCT/EP2009/060168 63 C58-C101 shall depict situations in which a longer (> 3 C atoms) side chain connection of a suitable diamine or diacid is involved in an amide bond. 5 Table 12: Representative Embodiments of Linker C
R
4
R
5 O R4 R' O R 4
R
9
R
4
R
5 [ R4 R7 R 3
R
9 I 1 11i 1 1 111 1 1 1 1 11 1ii 1 1 1 --- N-C- C-N-C- C-N-C--U--- --- N-C- C-N-C--C-Z-C-U-- I I I I H I R[ R 8 Rio R[ R 8 Ri 0 0-1 0-1 0-1 C1 C2
R
4
R
5
R
3
R
7 0 R 4 RR 0 R 4 7 R1 2
R
9 --- -C-C-Z-C-C-N-C-U--- I I N-C C-N-C CC-C-U-- I H [ R6RJ 1 1
R
6 1R RR R' 3
R
10 0-1 C3 C4
R
4
R
5 R1 2
R
7 0 R 4
R
9
R
4
R
5
R
3
R
7
R
3
R
9 I I aI || I | |I | | | | | --- N-C-C---C-C-C-N-C-U --- --- N-C-C-Z-C-C-Z--U--- I > I I I | I | |
R
6
R
13
R
8 Ri 0
R
6 H Ra H Ri 0 C5 C6
R
4
R
5
R
14 0 R 4
R
7
R
16
R
4
R
5 R14 R4 R16 R 7 | | | | | I | | | | | | | | | | --- N-C-C- C-N-C- -- --- N-C-C--C-N-C--C-U-- I I I I I I I I
R
6 R 15
R
6
R
1
R
17
R
8 L tj 01 c0-1 C7 C8
R
4
R
14
R
5 0 R 4
R
7
RI
6 R 14
R
5 0 R 4 RO] R7 | | | || l I | I | | | || I | 1 --- N-C-C- C-N-C- C- -- U--- --- N-C-C-C-N--C--C-U-- I I I 6 | 1 I 1
R
15
R
6
R
8
R
17 R R R 17 R L j0-1 u C9 C10 WO 2011/015241 PCT/EP2009/060168 64
R
4 R 5 FR14 R 3 R16l R 7 R 4
R
5 R 1 4 R 3 R 7 R 16l R 6
R
1 5 17 R 8 R 6 R 15 H R 8
[R
17 0-1 t U Cil C12
R
4
R
1 4
R
5
R
3
R
16
R
7
R
4
R
14
R
5
R
3
R
7 FR16]
R
15 R6 H 17
R
8
R
15
R
6 H R 8 [Rl 7 J U u C13 C14 R 4 R 5 R 1 4 R 1 2 R 6] R 7 R 4 R 5 R 14 R 1 2 R 7 [Rl6l --- N-C--C--C-CC-C-U---- --- N-C-C-C--C-C- C--U--
R
6
R
1 5 R 13 R 1 7 R 8
R
6
R
15 R 13 R 8 R 1 7 C15 C16 R 4 R 14 R 5 R 12 FRl6l R 7 R 4 R 1 4 R 5 R 1 2 R 7 [R16l R 15 R 6 R 1 3 R 1 7 R 8 R 1 5 R 6 R 13 R 8
[R
17 J U U C17 C18
R
4
R
5 R1 4
R
1 4 0 R 4
R
7 R1 6
R
4
R
5
R
1 4
R
4 0R 1
R
7
R
1 C II 1 -- NC-- R 14 R1 R4 16 R7 --- N-CC-C C--C -- u--- --- N-C-C-C-C-N-C C - 6R15 45 RJR 1 -A}R5 1 R17 R4417 0-11 C19 C20
R
4
R
5
R
14
R
14 0o R 4
R
6
R
7
R
4
R
1
RR
4 0 R 7
R
1 --- N-C-C-C-- - - --- N-C-C-C-CNC -u
R
6
R
15 R 5R 7uR 1 6 R sLR R 7-t C21. C2 2 WO 2011/015241 PCT/EP2009/060168 65
R
4
R
14
R
5 R 14 0 R 4
R
16 R R16 R 4
R
14
R
5
R'
4 0 R 4 [RJ R 7 I I I I | | I I I I II I I I | | | | I 1 --- N-C-C-C-C-N-C-C C-U--- --- N-C-C-C-C-N_-C-C-U-- I I I I I I | I | | I 1
R
15
R
6
R
1
R
7
R
8
R
1
R
15
R
6 R [R157 R 8 0-1 u C23 C24
R
4 R1 4
R
14 R5 O R4 R R ' R 4
R
14
R
14
R
5 0 R 4
R
0
R
7 R5 I I I 1 1 1 1 1 1 --- N-C-C |C I I | | | I || | | | --- N-C-C-C- C-N-C- C- - --- --- N-C-C-C-C-N-C-C C- U-- :4Iu - IIIII| | | 5 R15 R6 R R R 15
R
15
R
6
R
1 7 R'9 R] - 0-1 C25 C26
R
4
R
14
R
14
R
5 0 R 4 R ' R 7
R
4
R
5
R
14
R
14
R
3
R
7 [R --- N-C-C-C-C-N--C-C-U--- --- N-C-C-C-C-Z-C C U-- R R 15 R 1 6
R
7
R
8
R
6
R
1
R'
5 H R [R 17 1 u t C27 C28
R
4
R
5
R
1 4
R
14
R
3
R
16
R
7 Ril R R 5
R
4
R
14
R
3 R 16
R
7 --- I- - - - - - - - L U -- I I II I I I I I I --- N-C-C-C-C-Z-C-C- C U--- --- N-C-C-C-C-Z-C-C-C-U-- R R 15
R
1 H R R R 1 7
R
6
R
1 5 R 15 H R 17
R
17 R 0-1 C29 C30
R
4
R
1 4
R
5
R
1 4
R
3
R
7 R16 R 4
R
14
R
5
R
14
R
3
R
16
R
7 [R --- N-C-C-C-C-Z-C- C- U--- --- N-C-C-C-C-Z-C-C- C-U-- I 1 | 1 I I I 1 1 7 I I
R
1
R
6 Ri 5 H R 8
R
17 R R R 15 H R R 8 [R u 0-1 C31 C32
R
4
R
14
R
5
R
14
R
3
R
1 6 R 1 6 R 7
R
4
R
14
R
14
R
5
R
3
R
7 I I I I I I I I I II II II I--- N-C-C-C-C-Z-C~ U-- --- N-C-C-C-C-Z-C-C-C-U--- I N--ZC- C- I II I I I I IH1 1
R
15
R
6
R
1 5 H R 17
R
17
R
8
R
15
R
15
R
6 H R [R 1 t C33 C34
R
4
R
14
R
14
R
5
R
3
R
16
R
7 R 6l R 4
R
14
R
14
R
5
R
3 R 7 R R --- I- - - - -Z C C - U ... II I I I I I I I --- N-C-C-C-C-Z-C-C- C- - --- N-C-C-C-C-Z-C-C-C-U--
R
15
R
1 5
R
6 H R 17
R
8 R R 15 1 5 ' H 17 17 R 0-1 WO 2011/015241 PCT/EP2009/060168 66 C35 C36 R[4 R5 Ri1 R 1 R1 R7R R 4 R5 Ri 4
R
14
R
12
R
16
R
7 R1o I I I I I I I I | I I | |I N-C-C-C-C-C-C-C - --- --- N-C-C-C-C-C-C-C -C--U-- I I I I I I I I I I I II RR15 R 1 5
R
13
R
8 [R1 7
R
6 R1 5 R1 5 R1 3 R1 7
R
8 R17 t 0-1 C37 C38
R
4
R
5 R1 4
R
4 R1 2
R
1 6 7 4 1 4 5
R
14 R1 2
R
7 I I ~~ I I I I II- U U . --- I -C-C-C-C=C-C-C-C-UNC I I I I 6 15 R1 5
R
13
R
17 R1 7 8 R1 5 R R 15 R1 3
R
5
[R
7 u C39 C40
R
4 R1 4
R
5 R1 4 R1 2 R1 6
R
7 R 1 R 4 R1 4
R
5 R1 4
R
12 R1 6 R1 6
R
7 --- N-C-C-C-CCC-C-C -C UNCU-- R 5 R1 6 R1 5 1' 3 R1 7 1 3
R
7 -- I I I' I- -C C - 1
R
15
P
6
P
15
P
13
R
17
R
17
P
3 0-1 C41 C42
R
4 1 4 Ri 4
R
5 2
R
7 [p1 5 P 4 1 4 4
R
5 R1 2 R 1 6
R
7 R6] | I | | |I I | | | I I I II --- N-C-C-C-C-C-C-C U--- --- N-C-C-CC--C-C-C-C--U-- I I I a I I I I I I' I I II R1 5 R1 5
R
6
R
1 3
R
8
[R
7
R
15 R1 5
R
6
R
1 3
R
17 Ra R 1 7 t 0-1 C43 C44
R
4 R1 4 R1 4
R
5 R1 2 R1 6 R 6
R
7
R
4
|
5 | | | - -- --- N-C- C--C-N---U-- I- I I-C C C - - -C U - I I I 15 R15 R 6 R1 3
R
17 R1 7
R
8 R6 R R8 3 -5 -0-1 C45 C46 R4 R14 R 5 R4 R7 R 4
R
5 R14 R3 R 7 R7 --- -N-C--C-C-N-C--U- --- --- N-C- C--C-Z--C-i-C-U-- I I I I I| | R15; RS R R R'5 R 1 Rs 3~..3~-5 ~1 C47 0-1C C4 7 C4 8 WO 2011/015241 PCT/EP2009/060168 67
R
4 R 5 R 14 R 1 2 R 6]R 7 R 4
R
5 [R14 R 4 0 R 4
R
7 [R16 --- N-C--C--C-CC -C-U---- --- N-C-I-C-tN-C-N--C---
R
6
R
15 R 13 R 17 R 8
R
6 [R 1 j R 8 [R 17 3- t1-5 1-5 C4 9 C50
R
4 [R14lR5 R 4 0 R 4
R
7 T [6l R 4 R'lR5 R 4 0 R 4 [ RIlR 7 I II I 1 11 I I II I I I 1 11 1 1 'i i 1 --- C-C-N-C-N-C C U --- --- N C -tC-N-C-N- C C-Ulii 1I III I I I li
-R
15 J R 6 R [RI 7 ] R 15
R
6 [R 17 R 8 1-5 1-5 1-5 1-5 C51 C52 R 6 R 15R 17 R 8 1-5 1-5 C5 3 R 4 R 5 R14l0 R 4
R
7
R
1 6 4R -N-C-C -- C-N-C4-C5C-N-C-U-- R 6 R 15 R8R1 i t U C54 R 4
R
1 4 R 5 0 R 1 4R I I 1 1 1 1 --- C -C-C-NC C-CNC-U-- R 15
R
6 R8R1 i CS55 --- N-----C--- -------- C56 WO 2011/015241 PCT/EP2009/060168 68
R
4 R' R 14 0 R 4
R'
6
R
7 0 R 4
R
9 --- N-C C--C-N--C--C-C-N-C-U-- R6 R15 R17 R8 Rio t u C57
R
4 Rs R14 R3 R 7
R
16 0 R 4
R
9 I I I I | || I I --- N-C--C--C-Z-C- C--C-N-C-U--
R
8
R
1 5 H Rs R17 Rio t u C58 R 14
R
5
R
3
R
7 R16 0 R 4
R
9 |I | |I | IlI I | --- N-C- -C-C-Z-C--C--C-N-C-U-- I 1 8 I 1 R15 R H R 8 Ri R u u C59 R 4 R4 R 5
R
3 [ R16 R 7 0 R 4
R
9 JR I I iII I I 1 --- N--C- -C-C-Z--C--C-C-N-C-U-- .1 I | l|i 1i R15 R 6 H R 1 7
R
8
R
10 u u C60
R
4
R
5 RA R3 R 16
R
7 0 R4 R 9 I I || I | --- N-C- C--C-Z-4C--C-C-N-C-U-- I |II| 1
R
6 R1 5 H R17 R R 10 t u C61
R
4
R
5
R
14 O R 4
R
7
R
1 6
R
3
R
9 --- N-C- C--C-N-C- C--C-Z-U- - I | 1 7 1 |1| R 6 R15 Ra R1 H R1 t u C62 WO 2011/015241 PCT/EP2009/060168 69 R4 R 14
R
5 0 R4 R 7
R
16
R
3
R
9 --- N--C--C-C-N-C--C--C-Z-C-U-- I I | | | R 8
R
17 H R 1 0 R15 RG RS R H Ri u u C63 R4 R1 4
R
5 0 R 4
R
16
R
7
R
3
R
9 I I 1 1 1 1 1 1I --- N- C--C-C-N--C--C-C-Z-C-U--
R
6 | |I | R15 R6 R17 R8 H R 10 U U C64
R
4
R
5
R
7 R4 R16 R7 R 3 Rg I I | | | | | | --- N--C-C--C-C-Z--U-- R15 R17 R8 H R10 RRRH R 1 t u C65 R4 R 5 R4l R 3
R
7 Ri 3 R9 I I I I I I II --- N-C- C--C-Z-C- C--C-Z-C-U-- I I | I
R
6
R
15 H R 8 R17 H Rio t u C66
R
4
R
14
R
5
R
3 R 7
R
1 6
R
3 R9 C67 R4R14 R? 5 R 3 [Ri1l R 7
F?
3
R
9 I I I I I 1 I I I --- [N-C--C-C-Z-C- C-C-Z-C-U-- I | | | i | |i H R 17 J F 8 H F 1 0 R 15 R6 H RS R1 H Ri u u C68 WO 2011/015241 PCT/EP2009/060168 70 R 4
R
5
R
14
R
3
R
16
R
7 R 3
R
9 --- N-CJ+ 4R R I IZ-C---Zuu Rs 15H R17R8H Rio t u C69
R
4 R' FR14lO R 4
R
7 FR16 1 R12 R 9
R
6
[R
15 J R 8
[R
17 J R 13 Rio t u C70
R
4 [R14 1 R 5 0 R 4 R 7 [Ri1] R 1 2
R
9 --- N---C-C-N-CC-C --C-C-U-- [R15J R 6 R [R 17] R 13 Ri U U C71
R
4 R 14
R
5 0 R 4 R16lR 7 R 1 2
R
9 R 15 R 6 R 17 R 8
R
13 Rio U U C7 2
R
4
R
5 R 14 0 R 4 R 16 R 7
R
12
R
9 --- N-C -4--N-44C-CI'UU R15 R7 R8 R 13 Rio C73
R
4
R
5 R 14 R 12 R 7 -R 16 0 R 4
R
9 --- N-C---CCC. CNC-Ut U C7 4 WO 2011/015241 PCT/EP2009/060168 71 R 4 R 14
R
5 R 12 R 7 [R 16l R 4
R
9 --- N--C-C-C--C-C-fC CO-N-C-U-- R 15 RG RI 3 Ra R 17] Ri U U C75 R4 R4 R5R12 R16l R 7 0 R 4
R
9 --- N----CC--C-C-I-C-C-N-C-U-- U U C76 R' FR14 R 1 2
R
16 R 7 0 R 4
R
9 --- N---CC C--C C C-C-N-C-U--
R
6 R 15
R
1 3 R 17 R 8 Rio t u C7 7 R 4 R 5 [R 14 R 1 2 R 7 R 16 R 3 Rg I I II I I I I --- N-C--C-tC---CCC-Z-C-z-U---
R
6
[R
1 5 J R 13 R 8 R 17 H Rio t U C78
R
4
R
14
R
5
R
12
R
7
R
16
R
3
R
9 4R+R6R-C-R8CC--C-z-C--U-- R 15R 6 13R R 17 H Rio u U C79 R 4 [R14 R 5 R 1 2 [R 16 R 7 R 3
R
9 --- C -- C-C=C--C--C-C-Z--u--- [R 6 R 13 [17J 8 1 10 U U C80 WO 2011/015241 PCT/EP2009/060168 72
R
4 R' FR14 R 12 [R16l R 7 R 3
R
9 --- N-C -- C-C-C -C--C-C-Z--U---
R
6 [R1 5 R 13
[R
17 J Rs H Rio t U C81 R 4
R
5 FR141 R 12 R 7 R 1 6 R 12
R
9 --- N-C C--C--C-C--C- C--(-u-- Rs R 15
R
1 3 R 8 R 1 7 R1Ri t u C82
R
4 FR14l R 5 R 12
R
7 [R16l R 1 2
R
9
[R
1 5 J R 6 R 13
R
8
[R
1 7 J R 1 3 Rio U U C8 3 R4 R14R 5 R 12 R16l R 7 R 12
R
9 R1 R R 1 3
R
1 7
R
8
R
13 Rio U U C84 R 4
R
5 FR14 R 1 2 Ri16 R 7 R 12 RO
R
6
[R
15 R 1 3 R 17 JR 8 R 13 Rio t U C8 5 R R 5 R 14 R 3 R 7
R
1 6 R 12
R
9 --- N-C - C----C C= Uu t u C86 WO 2011/015241 PCT/EP2009/060168 73 R4 R14 R 5
R
3
R
7 R16l R 1 2
R
9 --- N--C--C-C-Z-C--C--C--C-C-U-- I I | I | > I R15 R H Rs R1 7
R
1 3 Ri 0 u u C87 R4 R14 R 5
R
3
R
16
R
7
R
12
R
9 --- N--C- -C-C-Z--C- -C-C---C-C-U-- I I | I |I I R15 R6 H R 817 R R 13
R
10 U U C88
R
4
R
5 R 1 R3 Ri6 R7 R 12 Rg --- N-C- C- -C-Z--C- -C- -C-C-U-- RR15 H R17 R8 R13 R10 t u C89
R
4 R 5 Rl4 R 4 0 R 7
R
16 0 R 4
R
9 I I I | II I Ih I I --- N-C--C--N-C-C- C- C-N-C--U-- R 6
R
1 5
R
8 R17 Rio 1-1 C90
R
4 R41 R 5
R
4 0 R 7 R16 0 R4 R9 |I | | | I | | |I --- N- C- -C-N-C-C- C- C-N-C--U-- I I I | |
[R
15
R
6
R
8
R
1 7 Ri 1-5t -j0-L C91 R4 R14 R5 R4 0 R 1 6 R 7 0 R4 R9 |I | | | | | I I | | | 1 --- N-C--C-N-C- C--C- C-N-C-U-- I | 1 II R5 R6 R 17 Rs Rio 1-5 t C92 WO 2011/015241 PCT/EP2009/060168 74 R 4 R5 R 14 R 4 0 R 16 R 7 0 R 4
R
9 --- N-C -- -N C -C - -C8- -U 1-5 t C9 3
R
4 R 5 [R14] R F16 R49 I I I I I I -j L 0-1 C94 R 4
R
1 4 R 5 R 7 FR16 R49 RU5 R 8
[R
17 4io C9 5 I I I I I I I I N - - - -C S C - -C - -C -U-- R 6 15 J [R 17 R 8 Ri U t - C97 WO 2011/015241 PCT/EP2009/060168 75
R
4
R
5 Ri 4 0 0 R 7 R O R4 R9 I I [ 1 || || 1 1 || | --- N-C- C--C-C-C--C- -C-N-C--U-- I |I 1 |
R
6
R
15
R
8
R
17
R
10 u t- - 0-1 C98
R
4 R R5 0 R7 R16 O R4 R9 --- N- -C--C-C-C-C-C-- C-N-C--U-- I | | | | R15 R 6 R 8
R
17 Rio u t -0-1 C99
R
4
R
1 4
R
5 0 0 R 16
R
7 OR4 R9 I I | 1 1 | R+15 R 4 R17 R84 Rio u t - -0-1 C100
R
4
R
5
R
14 0 0 R 16 R7 O R4 R9 I [I I k 1
N-C--C--C-C--C--C--C-N-C--U-
R R15 R17 R 8 Rio u ~t - -0-1 C101 According to the preceding explanations, products of type I contain at least two amide bonds. As mentioned in the introduction, tertiary amide containing products generally show 5 various ratios of cis and trans amide bond conformations in solution; this preference is in contrast to secondary amides that generally adopt trans conformations only. The occurrence of cis and/or trans conformations in macrocyclic natural products containing tertiary amides is well documented. In some 10 cases a rapid equilibration between the cis and trans amide bonds, the so-called "peptidyl cis trans isomerization", is WO 2011/015241 PCT/EP2009/060168 76 observed; whereas in other cases discrete cis and trans tertiary amide bonds are detected as two stable conformers in solution at room temperature. All possible stereoisomers, including atropisomers, and 5 distinct conformers or rotamers of macrocycles of type I are part of this invention. Within the general scope of building blocks A preferred radicals are: 10 Within the general scope of building blocks A preferred radicals are Al(al); A2(al); A3(al); A4(al); A5(al); A6(al); A7(al); A9(al); A10(al); A73(a2); A170(a4); A209(a7); 15 A240(alO); A272(alO); A532(a18); A609(a24); A612(a24) and A614(a24) (Table 13). Table 13: Preferred Building Blocks of Type A R R1 R1X , X I I X X, O 00 Al(al) A2(al) A3(al) A4(al) 1 R1 0 R 1 x x A5(al) A6(al) A7(al) A9(al) O RR X1 X O X x ' A10(al) A73(a2) A170(a4) A209(a7) WO 2011/015241 PCT/EP2009/060168 77 R7 R1
R
37 N X' NR N O -x -x R 38 0 A240 (alO) A272 (a1O) A532 (a18) A609(a24) R R 0 .3 O O A612(a24) A614(a24) Preferred building blocks of type B are B4(b3); B5(b3); B6(b3); B7(b3); B8(b3); B9(b3); B1O(b3); B12(b4); B13(b4); B14(b4); B15(b4); B16(b4) and B17(b5) (Table 14). 5 Table 14: Preferred Building Blocks of Type B RR2 RR R2 3 2 R23 N N R 2 N 'I 'I I R3 B4(b3) B5(b3) B6(b3) B7(b3) R 27 NN R1
R
2 N
R
3 N R 3 ' R3 B8 (b3) B9 (b3) B10 (b3) B12 (b4) R2,,R2 R2, R3 R1 N'R N RN
R
3
N
WO 2011/015241 PCT/EP2009/060168 78 B13 (b4) B14 (b4) B15 (b4) B16 (b4)
R
11 I N ' R3 B17 (b5) Preferred embodiments of linker C are shown in Table 15. Table 15: Preferred Linker of type C
R
4
R
5 0 R 4
R
7 0 R 4
R
9
R
4
R
5 0 R 4
R
7
R
3
R
9 I | | | | | | | | 1 | | | | | 1 | 1 --- N-C- C-N-C-- C-N-C-- U--- --- N-C- C-N-C- -C-Z--U--- R6 R8 Rio R6 R8 Rio 0-1 0-1 0-1 Cl C2
R
4
R
5
R
3
R
7
R
4 Rg R4 R5 R4 R7 R 12
R
9 R R R 0 R R I 1 I 11 1 1I I I I 1I 1 1I --- N-C- C-N-C±-C---u--- --- I-- - - - C N C U I I 1 H I R
R
6 H R R 13 R 0-1 C3 C4
R
4
R
5
R
12
R
7 0 R 4
R
9
R
4
R
5
R
3
R
7
R
3
R
9 I |I I || I | |I | | | | | --- N-C-C-C-C-C-N-C-U --- --- N-C-C-Z-C-C-Z--U--- I > I I | | | | |
R
6
RI
3 R8 R 1 R 6 H R 8 H R 10 C5 C6
R
4
R
5
R
14 0 R 4
R
7
R
1 G R4 R5 R14 O R4 R16 R 7 I I 1 1 1 1 1 1 1 1I --- N-C-C- C-N-C- C---U--- N-C-CC--C-N- C--C-U-- I I I I I I I
R
6
R
15 R 1 SR5R7R t d -1 -t C7 C8 WO 2011/015241 PCT/EP2009/060168 79
R
4
R
14
R
5 0 R 4
R
7
R
6
R
4
R
1 4
R
5 0 R 4 R1 R7 | | | I I | | | | | || | | 1 --- N-C-C-C-N-C- C---U--- --- N-C-C-C-N--C--C-U-- I I I I I I | R R R R R 15
R
6 RiJ R 8 .. t- 0-1 C9 C1O
R
4 R5 R14l R 3
R
16
R
7
R
4
R
5
R
14 R3 R7 16 --- N-C-C--C-Z-C-I-C-U--- --- N-C-C-C-Z-C- C--U-- I I I I | | I I I | I I
R
6 R15 H R 17
R
8
R
6
R
15 H Ra R17 . 0-1 . t u C1l C12
R
4
R
14
R
5
R
3
R
1 6
R
7
R
4
R
1 4
R
5
R
3
R
7 R16 I I I I I I I I I I I I I --- N-C-C-C-Z--C--U--- --- N-C-C-C-Z-C- C--U-- R15 R6 H R17 R8 R 15
R
6 H R 8 [ R 17 u u C13 C14
R
4
R
5
R
14
R
12 R16 R 7
R
4
R
5
R
14
R
12
R
7 [ R16l I I | I | | | |4i i| --- N-C- C--C---C C--C-U --- --- N-C-C-C---C-C- C- -U--
R
6
R
15
R
1 3 R17 R 8
R
6
R
15
R
13
R
8
R
1 7 0-1 t u C15 C16
R
4
R
14
R
5
R
12 R16 R 7
R
4
R
14
R
5
R
12
R
7 [ R 16 | | | I I | | | | Ii| --- N-C-C-C-C--C--C-U--- --- N-C-C-C-C-C- C--U-- I I I > I I I I I I i|
R
15
R
6
R
13
R
17
R
8
R
15
R
6
R
13 R 8
R
1 7 U U C17 C18
R
4
R
5
R
1 4 R14 O R4 R161] R 4
R
5
R
14
R
14 0 R 4
R
1 6 R 7 Rl --- N-C-C-C- C-N-C- C - -U--- --- N-C-C-C-C-N-C-C- C U--
R
6 R1 5 R15 R 8 R17 R 6
R
15
R
15
R
17
R
8 1Rl 7 t - 10-1 C19 C20 WO 2011/015241 PCT/EP2009/060168 80
R
4
R
5
R
14
R
1 4 0 R 4 Ri 6
R
7 R4 R14 R14 R 5 0 R 4
R
7
R
16 I I I 1 1 1 1I 1 1 --- N-C-C-C-C-N- C-U--- --- N-C-C-C-C-N-C-C--U-- R R R 15 17u R R R5 Re R8 R .. t- 0-1 C21 C25
R
4
R
14
R
14 R5 0 R 4
R
16
R
7 Ril R 4
R
14
R
14
R
5 0 R 4 R1' R 7 1 | | | | | | | | | 1 I | | 1 1 1 --- N-C-C-C-C-N-C-C C-t U--- --- N-C-C-C-C-N--C -C-U-- I I I I I I | | | | 1
R
15
R
15 Re R 17
R
8 R 17
R
15
R
15
R
6
R
1 7 J R 8 0-1 u C26 C27
R
4
R
5
R
14 R1 4
R
3
RR
4
R
5
R
14
R
4
R
3
R
16
R
7 [Ri I II I I I II I I I I I I II --- N-C-C-C-C-Z-C- C-U--- --- N-C-C-C-C-Z-C-C--CU-- 6 15 15 1 1 5 R | | 1 J7
R
6 Ri 5
R'
5 H R8 R R6 Ri R 5 H R 1 7 R [R1 7 t 0-1 C28 C29 R R R R R1 R1 RI I I I I I II I I I I I I I I --- N-C-C-C-C-Z-C;- C U-- R 4 R 5 R 4 R 14 R 3 R7 RR RR 4 R 14 R 14 R 5 R 3 R 7 R io --- N-C-C-C-C-Z-C-C-C-U--- N--CC--ZC C 6 15
R
1 5 H R 17
R
17 R8 R1 5
R
15 R H R [R1 7 t C30 C34
R
4 R1 4
R
14
R
5
R
3 R1e R 7 Ri R 4
R
14
R
14
R
5
R
3 R 1 Ri R NCCCCZCC -- C---U _-1-C-C-C-C-Z-C-C-C-U--
R
5
R
1 Re H R 7 R R R 15 R1 5 Re H R 17
R
7 R 0-1 C35 C36
R
4
R
5
R
4 R1 4 R1 2
R
7 Ri R 4
R
5 R1 4 R1 4
R
2
R
1 6 R 7 R16 --- N-C-C-C-C---C-C C- U--- --- N-C-C-C-C=-C-C-C C U-- | | | I I | | | |I I I I RG R 5 R1 5 R1 3
R
8
R
7 Re R1 5 R1 5 R1 3 R1 7 Re R1 t 0-1 C37 C38
R
4
R
5
R
14
R
14
R
2
R
16
R
1
R
7
R
4
R
1 4 R1 4
R
5 R1 2
R
7 R1 R4 R5 RI I I I III I I I I I I I --- N-C-C-C-C=C-C-C U-- --- N-C-C-C-C=C-C-C-C-U--- I I I I I
R
6 5
R
15
R
13
R
17
R
17 Re R1 5
R
5 Re R 1 Re [R 1 t WO 2011/015241 PCT/EP2009/060168 81 C3 9 C4 3
R
4
R
14
R
14
R
5 R 12
R
16 R 7 RI1 R 4
R
14 R 14
R
5 R 12
R
16
R
16 R 7 --- NC-C---CC-C-C C --- --- N-C-C-C----C-C-C-C-U-- R 15
R
15
R
6
R
1 3 R 17 Ra -R 17 J R 15 R's R 6
R
13 R 17 R 17
R
8 0-1 C4 4 C4 5
R
4
R
5 FR14 0 R 4
R
7
R
4 FR14lR5 0~ R 4
R
7 I I 1 11 1ii1 1 1i 1 --- N--C ~C -- C-- U- --- N-C-C -- C-N-CU---
R
6
[R
15
R
8
[R
15 J R 6 R 31 j0-1 3- L - C46 C4 7
R
4
R
5 FR14 R 3
R
1 6
R
7
R
4
R
5
R
14
R
12 Rl6l R 7 1 6 15 1 117 Is1 6 1
R
13 R 17 J R 3-5 t 3-5 C4 8 C4 9 R 4 R 'R 4 R 0 R 4 R RIR 4 FR lJ l R 5 R 4 o R 4 R R6 -R 15 R" -R R 1 R 6 RT 7 1-5 1-5 1-5 1-5 C50 C51.
R
4 R , R 5 R 0 R 4
R
1 RR RR R 1 4 ~ l R 16 R ~~~~~~I I I1 1 1 1 11 1 1 1 1 1 1 1 -- N-CCNC-N - --- --- N-C404 N-C-N--C C 1-5 1-5 1-5 1-5 C52 C5 3
R
4 Rl 5
R
14 0 R 4
R
7 Rl 16 0 Rl 4
R
9 --- NC-C -N-C- C - l 6 R5 R 1 i t U C54 WO 2011/015241 PCT/EP2009/060168 82
R
4 R 14
R
5 0 R 4 R 7 R 1 6 0 R 4 R9 I I 1 1 1 1 --- N- -C -- C-C-N-C- C- C-N-C-U-- I II || R 1 5 R R R 17 Rio U U C55
R
4 R 14
R
5 0 R 4 Rlr 6
R
7 0 R 4 R9 --- N--C- -C-C-N--C- -C-C-N-C-U-- I I | I R 15 R 6 R 17 R 8 Rio u U C56
R
4
R
5 F R14l 0 R 4
R
1 6 R 7 0 R 4
R
9 II|I || I | | || | | --- N-C C-- C-N- C-t--C--N-C-U-- I I | | R 6
R
1 5 R 17 R8 Rio t u C57
R
4
R
5 R14 R3 R 7 R 16 0 R4 R 9 |I I I I I --- N-C--C--C-Z-C--C- C-N-C-U-- 15 H R 8 1 10 RS 1 H RS R R1 t u C58 R4 R 14
R
5
R
3
R
7 R16 O R4 R 9 I I I I I 1 1 1I 1 1 --- N--C- -C-C-Z-C- C--C-N-C-U-- I I 1 I | 15 H R 1R8 7 10 u u C59 R4 R1 R5 R [3 R16 R 7 0 R 4 Rg II I II I I 1 --- N-C--C-C-Z- C--C-C-N-C-U-- I I |I| 1I R15 R 6 H R 1 7
R
8
R
1 0 U U C60 WO 2011/015241 PCT/EP2009/060168 83
R
4
R
5
R
14
R
3
R
1 6
R
7 0 R 4
R
9 --- N-C - C --- C - C N C U t U C61 R 4
R
5 [Rl4l0 R 4
R
7 R 16 R 3
R
9 I I 111 11 1 1 1 1 1 --- N-C- -C-- C-N-C- C- CCZ(-U--
R
6
R
15
R
8 R 1 7 Rio t U C62
R
14 R 5 0 R 4 R 7 R 16
R
3
R
9 N-C C-C-N--CC-Z-C-/U-U-- R 15R6R 8 R 17 H Rio u U C63 R4R14R 5 O R 4 FR16 1 R 7 R 3
R
9 I I I II I lI Ii I N-C C-C-N- -C-t C-C-Z---U-- 15 R R 17 R 8 H Rio u U C64 R 4 R 5 FR14 0 R 4
R
16 R 7
R
3
R
9 I I I II II I I --- N-C-tC-C N -- C C Z U - I II I R I I I I --- N-C- C -C ZC- C -5-U U
S
6 'R 15 'H RP 8
RP
1 7 i t U C66 WO 2011/015241 PCT/EP2009/060168 84 R4 R14 R 5
R
3
R
7
R
1 R3 R9 I | | I I N-C C-C-Z-C44-C -CZjC-U- R 15 R 6 H R 8 R 1 H Rio u u C67 R4 R 1 R 5
R
3 R16 R 7
R
3 Rg I I I II l Ii I I --- N--C- -C-C-Z--c-C-C-Z-C-u-- R15 R H R 17
R
8 H R 1 0 u u C68
R
4
R
5 R14 R3 R6 R7 R3 R 9 --- N-C- C-t-C-Z--C--C-C-Z-C-U-- I |I | ii| | | RD R 1 5 H R 17
R
8 H Ri 0 t u C69
R
4
R
5 Rl 4O R 4 R R 16 R12 Rg I |11| || | | | I | --- N-C--C-- C-N-C--C--C--C-C-U--- I II I I > | R 6
R
15
R
8 R 1 7
R
13
R
10 t u C70
R
4
R
14
R
5 0 R4 R 7 R 1 6 R 1 2
R
9 --- N-C--C-C-N-C--U-- 15 R 6 RB R 17 R 13 Rio u u C71
R
4
R
14
R
5 0 R 4
R
1 6 R 7
R
12
R
9 --- N--C--C-C-N--C- -C-C~--C-U-- R 15 R 6 R 17R8 R 13 Rio u u C7 2 WO 2011/015241 PCT/EP2009/060168 85
R
4
R
5 R 14 0 R 4
R
16
R
7 R 1 2
R
9 --- N-C C-CN-------u--- C73 R 4
R
5 FR14lR 12 R 7 [ R16l0 R 4
R
9 --- N-C --C-t C--C-C -IC--C-N-C-U--
R
6
[R
15 J R 1 3 R 8
[R
1 7] Rio t u C7 4 R 4 R 14
R
5 R 12 R 7 [R 16l R R 9 --- N--C-C-C- -C-C-C-O--N-C-U-- R 15 R 6
R
13
R
8 [R 17] Ri U U C75 R4 R14R 5 R 12 R16l R 7 0 R 4
R
9 --- N-C-C-C--C--C-I-C-C-N-C-U-- R1 R 6 R 13 R 17 R 8 Ri U U C76 R 4
R
5 [R14 R 12 Ri16R 7OR4 RO --- N-C--C-C-C-- -CN -U
R
6 [R15 R 1 3 R1 i t U C7 7 R 4
R
5 FR14l R 12 R 7 R 1 6 R 3 Rg --- N-C--C-tC=C-C C C-Z-C-/-U---
R
6
[R
15 J R 13 R 8 R 17 H Rio t U C78 WO 2011/015241 PCT/EP2009/060168 86 R4R14 R 5 R 12 R 7 R 16 R 3
R
9 --- N-C-C-C--C-C--C-C-Z-C-U-- R15R6 R 13
R
8 R 17 H Rio U U C79 R 4 FR14l R 5 R 1 2 [R 16 R 7 R 3
R
9
LR
5 6
R
1 3
R
17 J 8 H 0 u U C80
R
4 R 5 FR14 R 1 2 [R16l R 7 R 3
R
9 --- N--C- C--:C--IC-tC--C-Z--C-- R 6 [R1 5 R 13
[R
17 J R 8 H Rio t U C81
R
4 R' FR14l R 3 R 7 FR16 R 12
R
9 --- N-C- -C-t-C-Z-C -fC--C-'-C-Uu--
R
6 R H Rs [RI R 13
R
1 t U C86 R 4 R 1 4
R
5 R3 R 7 R 16 R 1 2
R
9 --- N-C-- -C Z-C --C-C -C U u -R R H R 8 -R R U U C87 R 4 14R 5R 3 R 16l R 7 R 12 Rg -- ~ ~ 4-- NZ--C-C=C-C-U-- R15 R 6 H [R 17 J R 8
RP
13 Rio U U C8 8 WO 2011/015241 PCT/EP2009/060168 87 R4 R 5 R14 R3 R16 R7 R 12
R
9 --- N-C- -C- -C-Z- -C- -C-C---C-C-U-- I I | || |9 I R- R15 H R 7 R8 R 13
R
10 t U C89 R4 R5 R R4 O R 7 R 16 O R 4
R
9 I I | 1 | | I 1 | | I I --- N-C- C--N-C-C- C---C-N-C- -U-- I I 1
R
6
R
8 R 1 R1 1-5
-
-0-1 C90
R
4 R141 R 5
R
4 0 R 7 R1S 0 R 4 R9 | | | | | I | | I I --- N--C- -C-N-C-C--C-- C-N-C- -U-- I I I I I
R
15
R
6
R
8 R 7 Rio 1-5 1~-5 t -0-1 C91
R
4 R14 R 5
R
4 0 Ri 6 R 7 0 R 4
R
9 | | |I I I ||1 1 I I --- N- C-C -CN-C- -C-- C-N-C--U-- R 15
R
6
R
17
R
8 Rio 1-5 t C92
R
4
R
5 R4 R4 O Ri6 R 7 0 R 4
R
9 I I | 1 | | 1 1 | | I I ---- -N -C-C--C--C-N-C- -U-- R 6 R 15 R 17 R8 Ri0 1-5 ~t C93 The preferred substituents of the preferred building blocks A, B and C are defined as: WO 2011/015241 PCT/EP2009/060168 88 R': H; F; Cl; Br; I; CF 3 ; OCF3; OCHF 2 ; NO 2 ; CN; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 5 - (CR 18
K
19 ) OR2 ; - (CRR) qNR4R2; - (CR 8 KR") NR4COOR; - (CR' 8 R) )NRCOR 2 2 ; - (CR'R") NRCONRR"; - (CRR') NR4SO 2 2 R; - (CRR") qNK 4
SO
2
NR
8 K"; - (CR"R'") qCOOR'; - (CRR') CONR4R2; - (CR 8 R") qSONRKRK"; - (CRR") PO (OR 21 ) 2; - (CR 8 R) COR 22 ; - (CR 8
R
9 ) qSO2R 2 ; - (CR'R") q0SO3R 2 ; - (CR 8
R
9 ) qK2; - (CK' 8 R) qKR; or 10 - (CRR 9 ) qR .
R
2 : H; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 15 - (CR 8
R
9 ) qOR20; - (CRR) qNR4R2; - (CR 8 R") 0 NR4COOR; - (CR'R') qNK 8
COR
2 ; - (CR'R") NR 4 CONRR; - (CRRR;) 4
NK
8
SO
2 R"; - (CR"R' 9 ) qNR4SO2NR 4 R"; - (CR'R 9 ) qCOOR 21 ; - (CR"R) qCONR4R; - (CR"R' 9 ) qSO2NJR 8 R"; - (CR' 8
R
9 ) qPO (OR 2 ) 2; - (CK'R'R) qCOR 22 ; - (CR1 8
R
9 ) qSO2R 2 ; 20 - (CRR 9 ) 4
R
24 ; - (CK 8 R") 4 R2; or - (CRR 9 ) R 2 .
R
3 : Defined as above.
R
4 : H; lower alkyl; lower alkenyl; lower cycloalkyl; lower 25 heterocycloalkyl; or a suitable N-protecting group. RK, R7 and R9 are independently defined as: H; F; CF; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower 30 heteroarylalkyl; - (CR' 8 R") ,OR; - (CRR 1 ') 2
NR
4 R'; - (CR 8 R") NR 4 COOR1; -(CRR )sNR4COR"; -(CR K ),NR4CONR4R ; -(CR"R) 3 NR4SO 0 2R - (CR' 8 R') NR4SO 2 NR4R"; - (CR" 8 R") COOR 22 ; - (CR'R') GCONR4R; - (CRR 9 ) 9
SO
2 NR4R ; - (CR 8
R
1 ) ,PO (OR 2 ) 2; - (CR 1 R") 'CORI'; 35 - (CR'R' 9 ) ,SORK; - (CR"R") R K 24 ; - (CR' 8
R'
9 ) qR; or - (CK'R") K 2
.
WO 2011/015241 PCT/EP2009/060168 89 R 6, R 8 and R U are independently defined as: H; CF 3 ; or lower alkyl. R": H; lower alkyl; lower alkenyl; lower cycloalkyl; 5 lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; a suitable protecting group; - (CR' 8
R'
9 ) OR 2 3; - (CR 8
R'
9 ) rNR 4 R2; - (CR' 8 R") rNR 4 COOR"; -1(CR 8 R") NR 4
CONR
4
R
2 ; - (CR'R"),rNR 4 SO2R'; - (CR"R") NR 4 SO2NR 4 R 2; - (CR' 8
R
9 ) qCOOR"; 10 - (CR'R") (CONRR ; - (CR'R") COR; - (CR'R") gSO 2 ; - (CR 8
R'
9 ) SOqNR 4 R27; - (CR' 8
R'
3 ) qR2 4 ; - (CR' 8
R
9 ) 0 R 5 ; or - (CR'R- 9 ) qR 2. R" and R' are independently defined as H; or lower alkyl. 15 R 4 and R"o are independently defined as: H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR'R 9 ) 2OR2 0 ; - (CR 8 R') 3
NR
4 R ; - (CR 8
R
9 ) JNR 4 COOR21; - (CR' 8
R
9 ) sNR 4 COR, - (CR 8
R-
9 ) 0
NR
4
CONR
4 R"; - (CR' 8
R'
9 ) NR 4 SOR; 20 - (CR"9R'") 'COOR; - (CRR") 4
CONR
4 R"; - (CR'R 9 ) qCOR 22 . R" and R' 7 are independently defined as: H; CF 3 ; lower alkyl. 25 R1: H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 9 R29) 0 OR; - (CR3R1) 3 NRe'; - (CR'R 30 ) jR"COORI; - (CR' 9 R") 2
NR
8 COR"; - (CR") sNR"CONR"R"; - (CR'R) 2 NR SOR" ; 30 - (CR'RF ) NR"SO2NR" '; - (CR R") gCOOR"; - (CR") qCONR"R 1 ; - (CR1R3 ) 'SO2R"R";
-(CR
9 R") gPO (OR") 2; -(CR"R') COR'; -(CR"R ) qSO2R'; - (CR2 9 R") R R ; - (CR"R'U) gR ; or - (CRR) 9R . 35 R' 9 : H; CF,; or lower alkyl.
WO 2011/015241 PCT/EP2009/060168 90
R
20 : H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; -(CR2RU ) rOR ; - (CR2R ) NR2R ; -(CR 2R3 ) rNR COOR 5 - (CR2 9
R
32 ) rNR COR ; - (CR'R 3 ) rNR 2
CONR
2
R
3 ; - (CR 2 RKU) rNR SORE ; - (CR 29 R U) QCOOR 2 1 - (CR 2
R
30 ) qCONR 2 8 R3 1 ; - (CR- R 3 U) QSO2NR K 31 ; - (CR 9
R
32 ) qCOR"; - (CR- R 3 ) qSO2R 2 ; - (CR 9
R'
0 ) qR 2 ; - (CR 2
R
30 ) qR 2 ; or - (CR R )qR 26 . 10 R 2 1 and R 23 : Defined as above.
R:
2 2 lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 15 - (CR R )OR'; - (CR R) )NR"RR; - (CR 9 RU) 2 NR 2 COOR; - (CR 9
R
32 ) NR 8 COR, -(CpRR )NR'CONRR; - (CRRKU) sNR S02R 2 ; - (CR 3 ) 2COOR 1 ; - (CR 29
R
3 0 ) SCONR 28
R;
31 - (CR 29
R
3 U) SO2NRR1 - (CR R 3 ") tCOR ; - (CRR 3 0 ) sSO2R 2 ; - (CR"R' 0 ) 9
R
2 ; - (CR R ) LR 28 ; or - (CRR 32 ) ,R 28 20
K
24 , R 2 and R 2 1: Defined as above.
K
27 and R: Defined as above. 25 R 29 : H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; (CR R ) OR ; - (CR 2
R
22 )sNRR 3 ; - (CRR 3 ) sNR 2 COORl; - (CR 3 3) ,NR 28
COR
2 ; - (CR 32
R
3 1) 2NR 2
CONR
2 R ; - (CR1 2
R
3 3) ,NR 28
SOR
23 ; 30 - (C 32 R) qCOOR 1 ; - (CR 2 3 ) CONR 8
R
31 ; - (CR1R2') qSO2NR 8
R
9 1 ; - (CRR 32 3 1) qPO (OR 2 ) 2; - (CR3 2 R- )COR 31 ; - (CR'R 3 ) qSO2R23; - (CR3R1) R 31
R
30 and R 3 3 : H; CF; lower alkyl. 35 R 3 and R: 3 2 Defined as above.
WO 2011/015241 PCT/EP2009/060168 91
R
3 4 and R 3 5 are independently defined as H; F; Cl; CF3;
OCF
3 ; OCHF 2 ; NO 2 ; CN; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower 5 heteroarylalkyl; - (CR" 9
R
3 0 ) qOR 31 ; - (CR2'R 3) qNRR 28 R - (CR 9
R
0 ) QNR COOR ; - (CR 2 9 R2) QNR COR ; - (CR 2
R
90 ) gNR 2
CONR
2 RE - (CR 9 R 3) qNR2 8
SO
2
R
23 ; - (CR 2 9
R
3 ) qCOOR 2 1 ; - (CR 2
R
2 ) qCONR 2
R
2 ; - (CR 9
R
0 ) 4 S0 2
NR
2
R
2 ; - (CR 2
R
20 ) COR 2 ; - (CR 2 R31 ) SOR 2 ; or - (CR 9 R30) R 1 . 10 R36: Defined as above.
R
2 3: H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; 15 lower heteroarylalkyl; a suitable N-protecting group; - (CR 9 R3) 'OR3; - 2(CR R0 ) NRR"; - (CRR 29 R ) NR"COOR'; - (CR"RS') rNR 28 COR3'; - (CRR0") rNR 28 CONR"R ; - (CR-"R") 1 NR" S0 2
R
2 ; - (CR""R") qCOOR"; - (CR""R") qCONR""R"; - (CR"R30) rSO 2 NR28R"; - (CR29R") qCOR"3; 20 - (CR 2
R
" ) 4 S0 2
R
2 2 ; or - (CR"R 2
)
4 R"-. R"8: H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 25 (CR 29 R3) qOR"; - (CR2"R 3) qNR 28 R"; - (CR 2 R3") qNR"COOR; 21 - (CRR qNR 0K (CR"R") NR CONR"R"; - (CR"R"") qCOOR"'; - (CR29R ") qCONR28R "; - (CR"R30) qCOR"1; or - (CR29R" ) R3R". R"; R4U; R4 ; R4 2 ; R3; R44; R45; R 4 6 ; R47; R 4 8 ; R'9 and R5U: 30 Defined as above. In the aforementioned preferred structures the variable heteroatom Z and the connector U are defined as: Z: 0; S(=O); or S(=0)2. 35 U: -C (=O) -; -NR4-C (=O) -; -C (=O) -C (=O)-; or -C (-OR") )-C (=O) -.
WO 2011/015241 PCT/EP2009/060168 92 Defined as above are: - Substituents that can be pairwise taken together and form optionally substituted cycloalkyl or heterocycloalkyl 5 moieties. - Structural elements that can form one of the groups of formulae H1l1-H118 (Table 9). - Variable heteroatoms Q, I, X and Y. - Indices q-u. 10 The above preferred structures include all possible stereoisomers, explicitly also including rotamers and atropisomers, of macrocycles of type I. Particularly preferred among the building blocks of type A are 15 Al (al) ; A2 (al) ; A3 (al) ; A4 (al) ; A5 (al) ; A6 (al) ; A7 (al) ; A9 (al); A10(al); A73(a2); A170(a4); A209(a7); A240(alO); A272(alO); A532(a18); A614(a24). For most of these building blocks, oxygen is the preferred nucleophilic moiety. However in the case of A170 it consists of a sulfur atom; and in the case of the three 20 building blocks A5-A7, both oxygen and sulfur derivatives are part of the invention (Table 16). Table 16: Particularly Preferred Building Blocks of Type A N RRN 00 Al~al) A2(al) A3(al) A4(al) R0
R
1 o0 N 0 A5(al) A6(al) A7(al) A9(al) WO 2011/015241 PCT/EP2009/060168 93 0 R1 0 N S1 0~ S 0 S A10 (al) A73 (a2) A170 (a4) A209 (a7)
R
37 R1 R O I 0.
R
38 A272 (a1O) A532 (a18) A614 (a24) Among the building blocks of type B particularly preferred are B7, B8, B9 and B-17 as shown in Table 17. 5 Table 17: Particularly Preferred Building Blocks of Type B R20-0 R20-0 R20-0 R20.o R3 R 3
R
3
R
3 B7-1 B7-2 B7-3 B7-4 O'-R20
OR
20 ,O'-R20 10-R20 NN N) R3 R3 R3 R3 B8-1 B8-2 B8-3 B8-4
R
27 R27 R27 R27 RiiN1 Rii-N' Rii-N' R11N1 N - N R3 ' R3 R 3
R
3 B9-1 B9-2 B9-3 B9-4 WO 2011/015241 PCT/EP2009/060168 94 R"i R" N N ' R3 ' R3 B17-1 B17-2 Particularly preferred embodiments of the linker C are listed in Table 18. 5 Table 18: Particularly Preferred Embodiments of Linker C
R
4
R
5 O R4 RI O R 4
R
9
R
4
R
5 [ R4 R7 R 3
R
9 I | || | 1 1 1 1 | 1 | | || | | 1 --- N-C- C-N-C--C-N-C--U--- --- N-C- C-N-C--C-Z-C-U-- I | I | | I| H I
R
6
R
8 Rio R[ R 8 Rio 0-1 0-1 0-1 Cl C2
R
4
R
5
R
3
R
7
R
4 Rg R4 R5 R4 R7 R 12
R
9 R R 0 R9I 1 11I 1 1 1 I I I 1I 1 1I --- N-C- C-N-C--C--C-C-U-- 6 H 110 R R 8
R
13 Rio 0-1 C3 C4
R
4
R
5
R
12
R
7 0 R 4
R
9
R
4
R
5
R
3
R
7
R
3
R
9 I |I I || I | |I | | | | | --- N-C-C-C-C-C-N-C-U --- --- N-C-C-Z-C-C-Z--U--- I > I I | | | | |
R
6
RI
3 R8 R 1 R 6 H R 8 H R 10 C5 C6
R
4
R
5
R
14 0 R 4
R
7
R
1 G R4 R5 R14 O R4 R 16
R
7 I I 1 1 1 1 1 1 1 1I --- N-C-C- C-N-C- C---U--- N-C-CC--C-N- C--C-U-- I II I I I I
R
6
R
15 R8 R 1 R6 R15 R17 R8 t d -1 -t C7 C8 WO 2011/015241 PCT/EP2009/060168 95
R
4
R
14
R
5 0 R 4
R
7
R
6
R
4
R
1 4
R
5 0 R 4 R1 R7 | | | I I | | | | | || | | 1 --- N-C-C-C-N-C- C---U--- --- N-C-C-C-N--C--C-U-- I I I I I I | R R R R R 15
R
6 RiJ R 8 .. t- 0-1 C9 C1O
R
4 R5 R14l R 3
R
16
R
7
R
4
R
5
R
14 R3 R7 16 --- N-C-C--C-Z-C-I-C-U--- --- N-C-C-C-Z-C- C--U-- I I I I | | I I I | I I
R
6 R15 H R 17
R
8
R
6
R
15 H Ra R17 . 0-1 . t u C1l C12
R
4
R
14
R
5
R
3
R
1 6
R
7
R
4
R
1 4
R
5
R
3
R
7 R16 I I I I I I I I I I I I I --- N-C-C-C-Z--C- -U--- --- N-C-C-C-Z-C- C--U-- R15 R6 H R17 R8 R 15
R
6 H R 8 [ R 17 u u C13 C14
R
4
R
5
R
14
R
12 R16 R 7
R
4
R
5
R
14
R
12
R
7 [ R16l I I | I | | | |4i i| --- N-C- C--C---C C--C-U --- --- N-C-C-C---C-C- C- -U--
R
6
R
15
R
1 3 R17 R 8
R
6
R
15
R
13
R
8
R
1 7 0-1 t u C15 C16
R
4
R
14
R
5
R
12 R16 R 7
R
4
R
14
R
5
R
12
R
7 [ R 16 | | | I I | | | | Ii| --- N-C-C-C-C--C--C-U--- --- N-C-C-C-C-C- C--U-- I I I > I I I I I I i|
R
15
R
6
R
13
R
17
R
8
R
15
R
6
R
13 R 8
R
1 7 U U C17 C18
R
4
R
5
R
1 4 R14 O R4 R161] R 4
R
5
R
14
R
14 0 R 4
R
1 6 R 7 Rl --- N-C-C-C- C-N-C- C - -U--- --- N-C-C-C-C-N-C-C- C U--
R
6 R1 5 R15 R 8 R17 R 6
R
15
R
15
R
17
R
8 1Rl 7 t - 10-1 C19 C20 WO 2011/015241 PCT/EP2009/060168 96 R 4 R 5 R 14
R
14 0 R 4 R ' 6 R 7 R 4 R1 4 R1 4 R 5 0 R 4 R 7 Rio I I I 1 1 1 1I 1 1 --- N-C-C-C-_-CU-- --- N-C-C-C-CNC -u R 6 1R 15 '1 51 L t- 0-1 C21. C25 R 4 R 14 R 14 R5 0 R 4
R
16 R 7 Ril R 4 R 14 R 14 Re 0 R 4 [Ril R 7 --- N-C-C-C-C-N-C-C C-tU --- --- N-C-C-C-C _-C -C-U-- R 15 R 15 Re R 17 R 8 -R 17 R 15 R 15 R 6
R
17
R
8 0-1 I C26 C2 7
R
4 R 5 R 14 R1 4 R 3 RR R7 R 1
R
4 Rl 16 R R --- N-C-C-C-C-Z-C- --- --- N-C-C-C-C-Z-C-C-C U
R
6
R
1
R
1 H R8R Re R 5 1 5 H R 1 7 Ra [R' 7 t 0-1 C28 C29 R R R R R1 R1 RI I I I I I II I I I I I I I I --- N-C-C-C-C-Z-C;- C U-- --- N-C-C-C-C-Z-C-C-C-U--- 6 1 1 1 I 7 R 15 R 1 5 H R 17 R 17 Re8 R1 5
R
15
R
6 H R8 [R 7 C30 C3 4 R 4 R1 4 R 14
R
5
R
3 Rie R 7 [R R 4
R
14
R
14
RR
3 R 1R6 R 7 NC CC CC-~-IU --- N-C-C-C-C-Z-C-C-C-U--
R
5
R
5 ReH R 7
R
8
L
1
JR
15 R1 5 Re H R 17 R1 7 Ra 0-1 C3 5 C36 R 4 R 5 R1 4 R 1 4 R 1 2
R
7 [i 4 1 5 4 1 4 1 2
R
1 7 r IITl R RI R R R R6III --- N-C-C-C-C::-C-C -C U --- --- N--CCC-CC CC _C u u RG R1 5 R1 5 R1 3
R
8
[
7 Re R1 5 R1 5 R1 3 R1 7 Re8R 7 t 0-1 C3 7 C3 8
RRR
14
R
14 R1 2 R 16
R
1 6 R 7 R 4 R M R1 4 Re R1 2 R 7 [RI R4 R5 RI I I I III I I I I I I I --- N-C-C-C-C=C-C-C U-- --- N-C-C-C-C=C-C-C-C-U--- I I I I I I RE R 1 5 R 13 R 17 R 17 Re R1 5 R1 5 Re R 1 Re [IR 1 WO 2011/015241 PCT/EP2009/060168 97 C39 C43
R
4
R
14
R
14 R5 R 12
R
16
R
7 R16 R 4
R
14
R
14
R
5
R
12
R
16
R
16
R
7 --- N-C-C-C-C-C-C-C- C- -U--- --- N-C-C-C-C---C-C-C-C-U--
R
15
R
15
R
6
R
13
R
17 Ra R 17
R
15
R
15
R
6
R
13
R
17
R
17
R
8 0-1 C44 C45
R
4
R
5 R14 0 R 4
R
7
R
4 R14 R5 O R 4
R
7 I I | | | | 1 1 1 1 | | | 1 --- N-C--C-- C-N-C--U--- --- N- C--C- C-N-C--U--
R
6
R
1 5
R
8
R
15
R
6 R8 3-5 - - 0-1 3-5 - - 0-1 C46 C47
R
4
R
5 R14 R 3
R
1 6
R
7
R
4
R
5
R
14
R
12 R6l R 7 --- N-C- ~C--- I-C-U--- --- N-C- C--C--C- C--C-U-- 1 |1 | |1 Is 1 6 1 13 I 7
R
6 R - H R7 R 6 R R 5
R
13 R - Ra 3-5 t 3-5 t C48 C49
R
4 R' R 14 0 R 4
R
7
R
1 6 0 R 4
R
9 --- C-N -C- C-N-C-U-- R6 R15 R8 R17 Ric t u C54
R
4
R
14
R
5 0 R 4
R
7
R
16 0 R 4
R
9 I I 1 | | I 1 1 I l 1 1 --- N- C--C-C-N-C- C--C-N-C-U--
R
15 Rs R8 R17 Rio u u C55
R
4
R
1 R5 O R 4 R6 R 7 0 R 4
R
9 I I | | I | | I | | | --- N- C--C-C-N- C- -C-C-N-C-U-- R1 R6 R17 R8 Ri u u C56 WO 2011/015241 PCT/EP2009/060168 98
R
4 R' R 14 0 R' R' 6 R 7 0 R 4
R
9 --- N-C C---C-CNCt u C57
R
4 RI [R14 1 R3 R 7
R'
6 0 R 4
R
9 I l i I I II I I --- N-C--C-f-C-Z-C-C C-N-U--
R
8 R 15 H Rs R 1 7 Rio t U C5 8
R
14
R
5
R
3
R
7 [R16 1 0 R 4
R
9 --- N-C-C-C-Z-C -- C---C--N---U-- R5RH R [R 7] U U C5 9 R4 R14R 5 R 3 [R6l R 7 0 R 4
R
9 JR I I iII I I 1 --- N-C-C-C-Z -- C-t C-C-N-C-U-- R15 R 6 H R 17 R 8 Rio u U C60 R 4 R 5 FR14 R3 R 16 R 7 0 R 4
R
9 I I I I I I 1 --- N-C -Z-C---CCz-4C-N-C-U R 6 [R1 5 H 7R8 Rio t U C61
R
4 R 5 R 14 0 R 4 R 7 R 16 R 3
R
9 --- N-C - C----CCZUU tU C62 WO 2011/015241 PCT/EP2009/060168 99 R4R 14
R
5 0 R 4 R 7 R 16
R
3
R
9 --- N-C-C-C-N-C--C-C-Z-C-U-- 6R 8
R
17 H R 1 0 U U C63
RR
14
R
5 0 R 4
R
16 R 7
R
3
R
9 I I 1 11 1 1 1I --- N4C4 C-C- N4-C4-C-CZU R15R 6 R7R 8 H Rio U U C64 R 4 R 5 R1 R4R6R 7 R 3 Rg I I 1I --- - C--N--CRJ4Ri: I I - RRRH R 1 t U C65
R
4
R
5 FR14l0 R 4
R
7 FR16lR12 Rg R 6
[R
15 J R 8 [R1 7 ] R 13 Rio t U C70
R
4
R
14
R
5 0 R 4 R 7 R 16
R
12
R
9 U U C71 R 4 R 14
R
5 0 R 4
R
16
R
7 R 1 2
R
9 U U C7 2 WO 2011/015241 PCT/EP2009/060168 100
R
4
R
5 R 14 0 R 4
R
16
R
7 R 1 2
R
9 --- N-C C-C N --- - -- -u--- C73 R 4
R
5 FR14lR 12 R 7 [ R16l0 R 4
R
9 --- N-C --C-t C--C-C -IC--C-N-C-U--
R
6
[R
15 J R 1 3 R 8
[R
1 7] Rio t u C7 4 R 4 R 14
R
5 R 12 R 7 [R 16l R R 9 --- N--C-C-C- -C-C-C-O--N-C-U-- R 15 R 6
R
13
R
8
[R
1 7 7]o U U C75 R4 R14R 5 R 1 2 R16l R 7 0 R 4
R
9 --- N-C-C-C--C--C-I-C-C-N-C-U-- R1 R 6 R 1 3 R 1 7 R 8 Ri U U C76 R 4
R
5 [R14 R 12 Ri16R 7OR4 RO --- N-C--C-C-C---CN -U
R
6 [R15 R 1 3 R1 i t U C7 7 R R R 4R O0R 7 FR 16 OR 4
R
9 I II I 11 1I I I --- N-C---NC-C ---- C NC-U-- R 6 R 5 R 8 LR 1 7i C90 WO 2011/015241 PCT/EP2009/060168 101
R
4 R14 R 5
R
4 0 R 7 R 16 0 R 4
R
9 | | |I | I | | I I --- N--C- -C-N-C-C-C- --C-N-C- -U-- Ji I I ±| R 15
R
6
R
8 R 17 Ri 1-5 t-j
-
C91 R 4 R R 5
R
4 0 R 16 R 7 0 R4 R9 I I I |II II I R15 R 6 R 1 7
R
8 Rio 1-5 t C92
R
4 R R R 7 0 R 4
R
9 I I 1 | I I --- N-C-C-NC C -CC-N-C- -U- - R 6 R 15 R 17 R 8Ri 1-5 t -0-1 C93 The particularly preferred substituents on the particularly preferred building blocks A, B and C are defined as: 5 R': H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO?; CN; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 10 - (CR' 8 R"9) qOR2 ; - (CR"R") qNR 4 R"; - (CR' 8 R") gNR 4 COR2. - (CR1 8 R9) NR 4
CONR
4 R "; - (CR'R") NR 4
SO
2 R; - (CR'"R'") NR 4 SO2NR 4 R"; - (CR' 8 R"9) qCOOR 2 ; - (CR' 8
R'
9 ) qCONR 4 R"; - (CR"R' 9 ) qSO2NR 4 R"; - (CRR") 2COR2; - (CR'1R- 9 ) qSO2R 23 ; - (CR- 8
R'
9 ) qR 24 ; - (CR1 8 R"9) qR 25 ; or - (CR 8 R"1) qR 26 . 15
R
2 : H; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; WO 2011/015241 PCT/EP2009/060168 102 lower heteroarylalkyl; (CR-8R19) qOR 20 ; - (CR"R") qNR4R,1; - (CRR 3 ) qNR 4 COR 2 2 - (CR'8R"1) qNR4CONR 4 R"; - ('CR"R') qNR 4
SO
2
R
2 3 ; - (CR" 3 R') NR 4 SO2NR 4 R"; - (CR'1R") qCOOR 2; - (CR"R') qCONR 4 R" ; - (CR"R") qSO2NR 4 R"; 5 - (CR 1 8
R
1 9 ) qCORE; - (CR"R 9 ) qSO2R 2 ; - (CR- 8 R') 4
R
24 ; - (CR'8R"9) qR 2 5 ; or - (CR 1 R") qR 2 6 .
R
3 : Defined as earlier hereinabove. 10 R4: H; lower alkyl; lower alkenyl; or a suitable N protecting group. R , R and R' are independently defined as: H; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; 15 aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; -(CR"R" 2OR20; -(CR'R"') 5 NRR; - (CR"R") sNRCOR2 - (CR"'R") NR4CONR"R"; - (CR"R"') sNR4SO2R"; - (CR"R") COOR'; - (CR"8R") qCONR4R"; - (CR"R") qSONR'R"; - (CR-R"') COR 2 ; - (CR'R"') qSO2R 3 ; 20 - (CR"'R") R""; - (CR'"R'") 4
R
25 ; or - (CR"') QR" . R6, R8 and R are independently defined as: H; CF 3 ; or
CH
3 . 25 R": H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; a suitable protecting group; - (CR"eR") OR2 3 ; - (CR"R")rNR4R' ; -(CR"R") rNR'CONR4R2; - (CRR 19) >NR4SO2R2; - (CR"R") COOR2; 30 - (CR"R") qCONR4R; - (CR"R") qCOR"; - (CR"1R"9) qR24; - (CRER") sR2; or - (CR"R') VR". R" and R" are independently defined as H; or lower alkyl. 35 R" and R" are independently defined as: H; F; CF3; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; WO 2011/015241 PCT/EP2009/060168 103 aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR' 8
R"
3 ) OR 2 0 ; - (CR'R") 0
NR
4 R"; - (CR 8 R") NR 4 COR< - (CR' 8 R"9) qCOOR 2; - (CR' 8 R") qCONR 4
R
11 . 5 R' 5 and R"1 are independently defined as: H; CF 3 ; or CH 3 .
R'
8 : H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 10 - (CR 2
R
33 ) 'OR 31 ; - (CR9R 3 ) NR 23
R
3 '; - (CR 3 0R) SNR 2 8C0R; - (CR 2
R
3 0 ) 3
NR
28
CONR
8
R
3 ; - (CR 2
R
30 ) SNR 8 O2R 23 ; - (CRNR) COOR 1 ; - (CR"R )2CONRRS0; R(CRDR0 ) 3 SC2NR 3
R
31 ; - (CR 2
R
3 1) qCOR 31 ; - (CR 29
R
30 ) qSO 2 3 ; - - 2 2 4
(CR
9
R
0 ) R; or - (CR R) 4
R
6 . 15
R'
3 : H; CE 3 ; or CH 3 .
R
20 : H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; 20 lower heteroarylalkyl; (CR 9
R
30 ) rOR 3 ; - (CR2 9 R 3 ) rNRR 2 8 R; - (CR 3 R 30) NR 28
COR
31 ; - 20 33 23 913l 3 _ (C 23 30) 21 93 p21 -I) C O - (CR R ) rNR CONR R ; - (CR R ) rNR SO2R ; - (CR"Rsc) 4 COOR<; - (CR 2 9R 3 ) 3CONR 28
R
3 ; - (CR 2
"R
30 ) qSO 2
NR
2 8
R
3 1 ; - (CR 2
R
30 ) COR3'; - (CR 2 R" ) SOR2S; - (CRR 3 )qR 3 4 ; - (CR"R ) qR; or - (CR"RE )qR 36 . 25
R
3 2 and R 2 : Defined as above
R
22 : lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower 30 heteroarylalkyl; (CR"9R 30 ) OR 3 1 ; - (CR 23
R>
0 ) NR 2
R
3 ; - (CR< 3
R
30 ) 9
NR
2 1COR 3 1 (CR 0 R"t) NR"CONR"R" 3 ; - (CRR " )
SNR
2 8S0 2 R 2; - (CR"R ) COOR 21 ; - (CR 3
R
3 ) sCONRR 31 ; - (CR 3 R0) S2NR 3 R 3 ; - (CR"'R 30 ) 9 COR ; - (CR 2
R
33 ) SSORE ; - (CR2R 0 ) tR4; - (CR" 3
R
3 3 ) R2 ; or - (CR"R 0 ) R 2 6 35 R2, R and R: Defined as above.
WO 2011/015241 PCT/EP2009/060168 104
K
27 and R 2 : Defined as above.
K
29 : H; F; CF 3 ; lower alkyl; lower alkenyl; lower 5 cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl;
-C
32
R
33 ) SO 3 1 ; (K R 3 1 ) SNR 2 1R 3 1 - (CR R )sOR ; - (CRER)N"E -(CR32R 33 ) SNR COR 1 ; - )(CR1R33) sNR 2 CONRR K 3 '; - (CRR 33 ) qCOOR 1 ; - (CR 3 R 3 3 ) qCONR 2 8R 3 1 ; - (CR 3 2
R
3 3 ) qCOR 3 1 ; - (CRR 3 2
R
3 3 qR 31 10
K
30 and R 33 : H; CF 3 ; or CH 3 .
K
3 1 and R 3 : Defined as above 15
K
34 and R 3 5 are independently defined as H; F; Cl; CF 3 ;
OCF
3 ; OCHF2; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower 20 heteroarylalkyl; - (CR" 3 K3 )qOR; - (CR 2 R 30 ) NR 2 8R 3 ; - (CRROO) gNR"
C
OR'l; - (CR R ) qNR"CONRR; - (CRRCC) qNR SO2R 3 ; - (CR29R 3 ) qCOOR 21 ; - (CR 2 9R") qCONR 2 8R; - (CR 2
"R
30 ) SO2NR 2 R'l; - (CR 2
R
0 ) qCOR 31 ; - (C 2 R9R ) So 2 R2 ; or - (CR 2
R
30 ) ,R 3 . 25
R
3 : Defined as in Part 3 "General Scope of the Invention".
R
37 : H; lower alkyl; lower alkenyl; lower cycloalkyl; 30 lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; a suitable N-protecting group; - (CR2R 30 ) OR 31 ; - (CR 2 9R 30 ) _NR 2 8R 3 ; - (CR 2 qR0) rNR 9 "COOR" ; - (CR 9 R") rNR"COR"; - (CR 2
R
3 ) rNR"CONR 9
R
3 1 ; - (CR 3 R) R COLOR; - (CR" 3 K) qCONR 3 R; - (CRR 3 ) CCOR; 35 or - (CR 2
R
33 ) gR 31
.
WO 2011/015241 PCT/EP2009/060168 105
R
38 : H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29
R
30 ) OR 31 ; - (CR 29
R"
0 ) qNR 2 aR 3 ; - (CR 29 RU) qNR 28
COR
31 ; 5 - (CR'R 3 0 ) qNR 8
CONR
8
R
1 ; - (CR 2 9
R
3 U) COOR 2 - (CRR2 R") qCONR 2 8 R3; - (CR- R 3 U) COR" 1 ; or -(CR2R3 ) R3.
R
39 ; R 4 0 ; R 4 ; R 42 ; R43; R 4 4 ; R 4 5 ; R 4 6 ; R 47 ; R 4 8 ; R4 9 and RKU: 10 Defined as above. In the aforementioned structures the variable heteroatom Z and the connector U are defined as: Z: 0; or S(=0)2. 15 U: -C (=0)-; -NR 4 -C (=0) -; or -C (=0) -C (=0)-. Defined as above are: - Substituents that can be pairwise taken together and form optionally substituted cycloalkyl or heterocycloalkyl 20 moieties. - Structural elements that can form one of the groups of formulae Hll1-H118 (Table 9). - Variable heteroatoms Q, I, X and Y. - Indices q-u. 25 The above particularly preferred structures include all posible stereoisomers, exlicity also rotamers and atropisomers, of macrocycles of type I. 30 Examples of, but not limited to, readily accessible substances that define possible subunits of the linker C are listed in Table 19. 35 Table 19: Substances Representing Subunits of Particularly Preferred Linkers C WO 2011/015241 PCT/EP2009/060168 106 Code Chemical Name Ala L-Alanine DAla D-Alanine Arg L-Arginine DArg D-Arginine Asn L-Asparagine DAsn D-Asparagine Asp L-Aspartic acid Asp D-Aspartic acid Cys L-Cysteine DCys D-Cysteine Glu L-Glutamic acid DGlu D-Glutamic acid Gln L-Glutamine DGln D-Glutamine Gly Glycine His L-Histidine DHis D-Histidine Ile L-Isoleucine DIle D-Isoleucine Leu L-Leucine DLeu D-Leucine Lys L-Lysine DLys D-Lysine Met L-Methionine DMet D-Methionine Phe L-Phenylalanine D he D-Phenylalanine Pro L-Proline "Pro D-Proline Ser L-Serine DSer D-Serine Thr L-Threonine DThr D-Threonine Trp L-Tryptophan "Trp D-Tryptophan Tyr L-Tyrosine WO 2011/015241 PCT/EP2009/060168 107 Code Chemical Name "Tyr D-Tyrosine Val L-Valine D Val D-Valine Apa 3-Amino-propanoic acid H-P3-HAla-OH (3S)-3-Amino-butyric acid H-P3-HVal-OH (3R)-3-Amino-4-methyl-valeric acid H-P3-HIle-OH (3R, 4S)-3-Amino-4-methyl-hexanoic acid H- p3-HLeu-OH (3S)-3-Amino-5-methyl-hexanoic acid H-P3-HMet-OH (3S)-3-Amino-5-methylthio pentanoic acid (3S)-3-Amino-4-(4'-hydroxyphenyl)-butyric H-f 3 -HTyr-OH acid (3S)-3-Amino-4-(imidazole-4'-yl)-butyric H- 3 -HHis-OH acid H- p3-HPhe-OH (3S)-3-Amino-4-phenyl butyric acid H-p3-HTrp-OH (3S)-3-Amino-4-(indol-3'-yl)-butyric acid H- p3-HSer-OH (3R)-3-Amino-4-hydroxy-butyric acid H- p-HAsp-OH 3-Amino-pentanedioic acid H-P3-HGlu-OH (3S)-3-Amino-hexanedioic acid H- p3-HLys-OH (3S)-3,7-Diamino-heptanoic acid H- p3-HArg-OH (3S)-3-Amino-6-guanidino-hexanoic-acid H-p3-HCys-OH (3R)-3-Amino-4-mercapto-butyric acid H- p3-HAsn-OH (3S)-3-Amino-4-carbamoyl-butyric acid H-P'-HGln-OH (3S)-3-Amino-5-carbamoyl-pentanoic acid H- p3-HThr-OH (3R,4R)-3-Amino-4-hydroxy-pentanoic acid Gaba 4-Amino-butyric acid H-y t -DiHAla-OH (4S)-4-Amino-pentanoic acid H-y 4 -DiHVal-OH (4R)-4-Amino-5-methyl-hexanoic acid H-y 4 -DiHIle-OH (4R, 5S)-4-Amino-5-methyl-heptanoic acid H-y 4 -DiHLeu-OH (4R)-4-Amino-6-methyl-heptanoic acid H-y 4 -DiHMet-OH (4R)-4-Amino-6-methylthio-hexanoic acid (4R)-4-Amino-5-(4'-hydroxyphenyl) pentanoic acid H-y4-DiHHis-OH (4R) -4-Amino-5-(imidazole-4'-yl) pentanoic acid H-y 4 -DiHPhe-OH (4R)-4-Amino-5-phenyl-pentanoic acid WO 2011/015241 PCT/EP2009/060168 108 Code Chemical Name (4R)-4-Amino-5-(indol-3'-yl)-pentanoic H-y 4 -DiHTrp-OH ai acid H-y -DiHSer-OH (4R)-4-Amino-5-hydroxy-pentanoic acid H-y 4 -DiHAsp-OH (4R)-4-Amino-hexanedioic acid H-y 4 -DiHGlu-OH 4-Amino-heptanedioic acid H-y 4 -DiHLys-OH (4S)-4,8-Diamino-octanoic acid H-y 4 -DiHArg-OH (4S)-4-Amino-7-guanidino-heptanoic-acid H- 4 -DiHCys-OH (4R)-4-Amino-5-mercapto-pentanoic acid H-y 4 -DiHAsn-OH (4R)-4-Amino-5-carbamoyl-pentanoic acid H-y 4 -DiHG1n-OH (3S)-3-Amino-5-carbamoyl-hexanoic acid H-y 4 -DiHThr-OH (4R, 5R)-4-Amino-5-hydroxy- hexanoic acid Cit L-Citrulline DCit D-Citrulline Orn L-Ornithine DOrn D-Ornithine tBuA L-t-Butylalanine DtBuA D-t-Butylalanine Sar Sarcosine Pen L-Penicillamine DPen D-Peniciliamine tBuG L-tert.-Butylglycine "tBuG D-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine D4AmPhe D-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine "3AmPne D-meta-Aminophenylalanine 2AmPhe L-ortho-Aminophenylalanine "2AmPhe D-ortho-Aminophenylalanine Phe (mC (NH2) =NH) L-meta-Amidinophenylalanine "Phe (mC (NH,) =NH) D-meta-Amidinophenylalanine Phe (pC (NH 2 ) =NH) L-para-Amidinophenylalanine "Phe (pC (NH,) =NH) D-para-Amidinophenyialanine Phe (mNHC (NH,) =NH) L-meta-Guanidinophenylalanine DPhe (mNHC (NH2) =NH) D-meta-Guanidinophenylalanine WO 2011/015241 PCT/EP2009/060168 109 Code Chemical Name Phe (pNHC (NH,) =NH) L-para-Guanidinophenylalanine DPhe (pNHC (NH 1 2) =NH) D-para-Guanidinophenylalanine 2Pal (2S)-2-Amino-3-(pyridine-2'-yl)-propionic acid D2Pa1 (2R -2-Amino-3-(pyridine-2'-yl)-propionic acid 4Pal (2S)-2-Amino-3-(pyridine-4'-yl)-propionic acid D4Pa1 (2R -2-Amino-3-(pyridine-4'-yl)-propionic acid Phg L-Phenylglycine DPhg D-Phenylglycine Cha L-Cyclohexylalanine DCha D-Cyclohexylalanine
C
4 al L-3-Cyclobutylalanine
DC
4 al D-3-Cyclobutylalanine Coal L-3-Cyclopentylalanine D C 5 al D-3-Cyclopentylalanine Nle L-Norleucine 1 Nle D-Norleucine 2-Nal L-2-Naphthylalanine D2Nal D-2-Naphthylalanine 1-Nal L-1-Naphthylalanine DlNal D-1-Naphthylalanine 4ClPhe L-4-Chlorophenylalanine '4ClPhe D-4-Chlorophenylalanine 3ClPhe L-3-Chlorophenylalanine "3ClPhe D-3-Chlorophenylalanine 2ClPhe L-2-Chlorophenylalanine "2ClPhe D-2-Chlorophenylalanine 3,4Cl2Phe L-3,4-Dichlorophenylalanine D ,4C 2 Phe D-3,4-Dichlorophenylalanine 4FPhe L-4-Fluorophenylalanine "4FPhe D-4-Fluorophenylalanine 3FPhe L-3-Fluorophenylalanine D3FPhe D-3-Fluorophenylalanine 2FPhe L-2-Fluorophenylalanine WO 2011/015241 PCT/EP2009/060168 110 Code Chemical Name "2FPhe D-2-Fluorophenylalanine Thi L-f-2-Thienylaianine DThi D-f-2-Thienylalanine Tza L-2-Thiazolylalanine DTza D-2-Thiazolylalanine Mso L-Methionine sulfoxide DMSO D-Methionine sulfoxide AcLys N-Acetyllysine DAcLys N-Acetyl-D-lysine Dap 2,3-Diaminopropionic acid DDap D-2,3-Diaminopropionic acid Dab 2,4-Diaminobutyric acid DDab (2R)-2,4-Diaminobutyric acid Dbu (2S)-2,3-Diamino-butyric acid "Dbu (2R)-2,3-Diamino-butyric acid Abu y-Aminobutyric acid (GABA) Aha s-Aminohexanoic acid Aib a-Aminoisobutyric acid Cyp 1-Amino cyclopentane carboxylic acid Y(Bzl) L-O-Benzyltyrosine DY(Bzl) D-O-Benzyltyrosine (3S)-2-Amino-3-(1'-benzylimidazole-4' yl)-propionic acid D (3R)- 2-Amino-3-(l'-benzylimidazole-4' yl)-propionic acid Bip L-(4-phenyl)phenylalanine DBip D-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine "S(Bzl) D-O-Benzylserine T(Bzl) L-O-Benzylthreonine "T(Bzl) D-0-Benzylthreonine alloT (2S, 3S)-2-Amino-3-hydroxy-butyric acid DallOT (2R, 3S)-2-Amino-3-hydroxy-butyric acid (2S, 3R)-2-Amino-3-hydroxy-4-methyl pentanoic acid DLeu3OH (2R, 3R)-2-Amino-3-hydroxy-4-methyl pentanoic acid hAla L-Homo-alanine WO 2011/015241 PCT/EP2009/060168 111 Code Chemical Name "hAla D-Homo-alanine hArg L-Homo-arginine DhArg D-Homo-arginine hCys L-Homo-cysteine DhCys D-Homo-cysteine hGlu L-Homo-glutamic acid DhGlu D-glutamic acid hGln L-Homo-glutamine DhGln D-Homo-glutamine hHis L-Homo-histidine DhHis D-Homo-histidine hIle L-Homo-isoleucine DhIle D-Homo-isoleucine hLeu L-Homo-leucine DhLeu D-Homo-leucine hNle L-Homo-norleucine Dh14le D-Homo-norleucine hLys L-Homo-lysine DhLys D-Homo-lysine hMet L-Homo-Methionine "hMet D-Homo-Methionine hPhe L-Homo-phenylalanine "hPhe D-Homo-phenylalanine hSer L-Homo-serine DhSer D-Homo-serine hThr L-Homo-threonine DhThr D-Homo-threonine hTrp L-Homo-tryptophan "hTrp D-Homo-tryptophan hTyr L-Homo-tyrosine DhTyr D-Homo-tyrosine hVal L-Homo-valine DhVal D-Homo-valine hCha L-Homo-cyclohexylalanine "hCha D-Homo-cyclohexylalanine WO 2011/015241 PCT/EP2009/060168 112 Code Chemical Name Bpa L-4-Benzoylphenylaianine DBpa D-4-Benzoylphenylalanine OctG L-Octylglycine DOctG D-Octyiglycine (3S)-1,2,3,4-Tetrahydroisoquinoline-3 Tic carboxylic acid Tic(3R)-1,2,3,4-Terahydroisoquinoine-3 carboxylic acid Tic (3S)-1,2,3,4-Tetrahydroisoquinoline-3 carboxylic acid D Ti(1K)-1,2,3,4-Tetrahydroisoquinoline-1 carboxylic acid D(2S, 3aS, 7a3)-1-Octahydro-1H-indolie-2 carboxylic acid DOiC (2R, 3aS, 7aS)-1-Octahydro-1H-indole-2 carboxylic acid S(2S, 4S) -4-Amino-pyrrolidine-2-carboxyic caboylccacid (2K, 4S)-4-Amino-pyrrolidine-2-carboxylic D4AmPyrrl ai acid S(2S, 4S -4-Amino-pyrrolidine-2-carboxylic 4AmPyrrl ci acid (2R, 4R)-4-Amino-pyrroiidine-2-carboxylic D4AmPyrr2 ai acid (2S, 4R)-4-Phenyl-pyrrolidine-2 carboxylic acid D 4PhePyrr (2, 4R)-4-Phenyl-pyrrolidine-2 carboxylic acid S(2S, 4S)-4-Phenyl-pyrrolidine-2 carboxylic acid D 4PhePyrr2 (2R, 4S)-4-Phenyl-pyrrolidine-2 carboxylic acid S(2S, 5R) -5-Phenyl-pyrrolidine-2 PhePyrrcarboxylic acid D5 Ph~yrrl(2K, 5K) -5-Phenyl-pyrrolidine-2 carboxylic acid (2S, 5S)-5-Phenyl-pyrrolidine-2 carboxylic acid D (2, 5S)-5-Phenyl-pyrrolidine-2 carboxylic acid 4Hypl (4S) -L-Hydroxyproline D 4Hyp5 (4S)-D-Hydroxyproline 4Hyp2 (4K)-L-Hydroxyproline "4Hyp2 (4K)-D-Hydroxyproline 4Mpl (4S)-L-Mercaptoproline D4Mpl (4S)-D-Mercaptoproline WO 2011/015241 PCT/EP2009/060168 113 Code Chemical Name 4Mp2 (4R)-L-Mercaptoproline D4Mp2 (4R)-D-Mercaptoproline Pip L-Pipecolic acid DPip D-Pipecolic acid H-P3-HCit-OH (3S)-3-Amino-6-carbamidyl-hexanoic acid H-fl-HOrn-OH (3S)-3,6-Diamino-hexanoic acid H-p3-HtBuA-OH (3S)-3-Amino-5,5-dimethyl-hexanoic acid H- p 3 -HSar-OH N-Methyl-3-amino-propionic acid (3R)-3-Amino-4-methyl-4-mercapto H-1-HPen-OH pentanoic acid H-$3 -HtBuG-OH (3R)-3-Amino-4,4-dimethyl-pentanoic acid (3S)-3-Amino-4-(4'-aminophenyl)-butyric H-f 3 -H4AmPhe-OH acid (33)-3-Amino-4-(3'-aminophenyl)-butyric H-f-H3AmnPhe-OH acid (3S)-3-Amino-4-(2'-aminophenyl)-butyric H-f-H2AmnPhe-OH acid H-fl>- (3S)-3-Amino-4-(3'-amidinophenyl)-butyric HPhe (mC (NH2) =NH) -OH acid H-fl>- (3S)-3-Amino-4-(4'-amidinophenyl)-butyric HPhe (pC (NH2) =NH) -OH acid H- 3 (3S)-3-Amino-4-(3'-guanidinophenyl) HPhe (mNHC (NH2) =NH) -OH butyric acid
H-P
3 (3S)-3-Amino-4-(4'-guanidino-phenyl) HPhe (pNHC (NH2) =NH) -OH butyric acid (3S)-3-Amino-4-(pyridine-2'-yl)-butyric H-$l -H2Pal-OH acid (3S)-3-Amino-4-(pyridine-4'-yl)-butyric H-f 3 -H4Pal-OH acid H-fl-HPhg-OH (3R)-3-Amino-3-phenyl-propionic acid H-fl-HCha-OH (3S)-3-Amino-4-cyclohexyl-butyric acid H-fl-HC 4 al-OH (3S)-3-Amino-4-cyclobutyl-butyric acid H-fl>-HCeai-OH (3S)-3-Amino-4-cyclopentyl-butyric acid H-fl-HNie-OH (3S)-3-Amino-heptanoic acid H-f 3 -H2Nal-OH (3S)-3-Amino-4-(2'-naphthyl)-butyric acid H-f 3 -HlNal-OH (3S)-3-Amino-4-(1'-naphthyl)-butyric acid (3S)-3-Amino-4-(4'-chlorophenyl)-butyric H-fl-H4ClPhe-OH ai acid (3S)-3-Amino-4-(3'-chlorophenyl)-butyric H-f 3 -H3ClPhe-OH acid WO 2011/015241 PCT/EP2009/060168 114 Code Chemical Name (3S)-3-Amino-4-(2'-chlorophenyl)-butyric H-fH2CPhe-OH acid (3S)-3-Amino-4-(3',4'-dichlorophenyl) H-13-H3, 4Cl 2 Phe-OH butyric acid (3S)-3-Amino-4-(4'-fluorophenyl)-butyric H-Ps-H4FPhe-OH acid (3S)-3-Amino-4-(3'-fluorophenyl)-butyric H-f3-H3FPhe-OH acid (3S)-3-Amino-4-(2'-fiuorophenyl)-butyric H-f -H2FPhe-OH acid H- 3-HThi-OH (3R) -3-Amino-4- (2' -thienyl) -butyric acid (3R)-3-Amino-4-(2'-thiazolyl)-butyric H-J3 3 -HTza-OH acid (3R)-3-Amino-4-methylsulfoxyl-butyric H-f3 3 -HMso-OH acid H- 3 -HAcLys-OH (3S)-7-Acetylamino-3-amino-heptanoic acid H-3 3 -HDpr-OH (3R) -3, 4-diamino-butyric acid H-j3-HA2Bu-OH (3S)-3,5-Diamino-pentanoic acid H-p3-HDbu-OH (3K) -3, 4-Diamino-pentanoic acid H-3 3 -HAib-OH Amino-dimethyl acetic acid H-$3-HCyp-OH 1-Amino-cyclopentane-1-yl-acetic acid (3S)-3-Amino-4-(4'-benzyloxyphenyl) H-1-HY (Bzl) -OH butyric acid (3S)-3-Amino-4-(1'-benzylimidazole-4'
H-J
3 -HH (Bzl) -OH yl) -butyric acid H-P3-HBip-OH (3S) -3-Amino-4-biphenylyl-butyric acid H-f 3 -HS (Bzl) -OH (3S)-3-Amino-4-(benzyloxy)-butyric acid (3R, 4R)-3-Amino-4-benzyloxy-pentanoic H-f 3 -HT (Bil) -OH acid H- 3-HalloT-OH (3R, 4S)-3-Amino-4-hydroxy-pentanoic acid (3R, 4R)-3-Amino-4-hydroxy-5-methyl H-f 3 -HLeu30H-OH hexanoic acid H-$3-HhAla-OH (3S)-3-Amino-pentanoic acid H-3 3 -HhArg-OH (3S) -3-Amino-7-guanidino-heptanoic acid
H-P
3 -HhCys-OH (3K)-Amino-5-mercapto-pentanoic acid H-P3-HhGlu-OH (32) -3-Amino-heptanedioic acid H-r -HhGln-OH (3S)-3-Amino-6-carbamoyl hexanoic acid (3S)-3-Amino-5-(imidazole-4'-yl) H-f-HhHis-OH pentanoic acid H-$3-HhIle-OH (32, 5S)-3-Amino-5-methyl-heptanoic acid H- 3-HhLeu-OH (32) -3-Amino-6-methyl-heptanoic acid WO 2011/015241 PCT/EP2009/060168 115 Code Chemical Name
H-P
3 -HhNle-OH (32) -3-Amino-octanoic acid H-P3-DiAoc-OH (32) -3, 8-Diamino-octanoic acid H-$3-HhMet-OH (3S)-3-Amino-6-methylthio-hexanoic acid H-P3-HhPe-OH (3S) -3-Amino-5-phenyl-pentanoic acid
H-P
3 -HhSer-OH (3S)-3-Amino-5-hydroxy-pentanoic acid H-P3-HhThr-OH (3S, 5R)-3-Amino-5-hydroxy-hexancic acid (3S)-3-Amino-5-(indol-3'-yl)-pentanoic
H-J
3 -HhTrp-OH acid (3S)-3-Amino-5-(4'-hydroxyphenyl) H-f 3 -HhThr-OH pentanoic acid H-P3-HhCha-OH (32) -3-Amino-5-cyclohexyl-pentanoic acid (3S)-3-Amino-4-(4'-benzoylphenyl)-butyric H--HBpa-OH acid H-P3-HOctG-OH (32) -3-Amino-undecanoic acid H-$3 -HN1e-OH (32) -3-Amino-heptanoic acid 3 O .(3S)-1,2,3,4-Tetrahydroisoquinoline-3-vl H- 3 -HTic-OH acetic acid (12)-1,2,3,4-Tetrahydroisoquinoline-1 H-j 3 -HTiq-OH acetic acid 3 . (2S, 3aS, 7aS)-1-Octahydro-1H-indole-2 H-J-HOic-OH yl-acetic acid (2S, 4S)-4-Amino-pyrrolidine-2-acetic H-J-H4AmPyrrl-OH acid (2S, 4R)-4-Amino-pyrrolidine-2-acetic H-$3 3 -H4AmPyrr2-OH acid (2S, 4R)-4-Phenyl-pyrrolidine-2-acetic H-1-H4PhePyrr1-OH acid (2S, 4S)-4-Phenyl-pyrrolidine-2-acetic H-j3 3 -H4PhePyrr2-OH acid (2S, 5R)-5-Phenyl-pyrrolidine-2-acetic H-j3 3 -H5PhePyrr1-OH acid (2S, 5S)-5-Phenyi-pyrrolidine-2-acetic H- 3 -H5PhePyrr2-OH acid (2S, 4S)-4-Hydroxy-pyrrolidine-2-acetic H-P3-H4Hypl-OH acid (22, 4R)-4-Hydroxy-pyrrolidine-2-acetic H-P3-H4Hyp2-OH acid (2R, 4S)-4-Mercapto-pyrrolidine-2-acetic H-j 3 -H4Mp1-OH acid (2R, 4R)-4-Mercapto-pyrrolidine-2-acetic
H-J
3 -H4Mp2-OH acid H-P3-HPip-OH (2S) -piperidine-2-acetic acid H-p3-HPro-OH (2S) -pyrrolidine-2-acetic acid H- '-H Dro-OH (2R)-pyrrolidine-2-acetic acid WO 2011/015241 PCT/EP2009/060168 116 Code Chemical Name Ahb 4-Amino-2-hydroxy butyric acid H-y 4 -DiHCit-OH (4S)-4-Amino-7-carbamidyl-heptanoic acid H-y 4 -DiHOrn-OH (4S)-4,7-Diamino-heptanoic acid H-y 4 -DiHtBuA-OH (4R)-4-Amino-6,6-dimethyl-heptanoic acid H-y 4 -DiHSar-OH N-Methyl-4-amino-butyric acid (4R)-4-Amino-5-methyl-5-mercapto-hexanoic H-y 4 -DiHPen-OH ai acid H-y 4 -DiHtBuG-OH (4R)-4-Amino-5,5-dimethyl-hexanoic acid 4 (4R)-4-Amino-5-(4'-aminophenyl)-pentanoic H-y 4 -DiH4AmPhe-OH ai acid 4 (4R)-4-Amino-5-(3'-aminophenyl)-pentanoic H-y 4 -DiH3AmPhe-OH ai acid 4 (4R)-4-Amino-5-(2'-aminophenyl)-pentanoic H-y 4 -DiH2AmPhe-OH ai acid H-y4 (4R)-4-Amino-5-(3'-amidinophenyl) DiHPhe (mC (NH 2 ) =NH) -OH pentanoic acid H-y4- (4R)-4-Amino-5-(4'-amidinophenyl) DiHPhe (pC (NH 2 ) =TH) -OH pentanoic acid H-y DiHPhe(mNHC(NH)=NH)- (4R)-4-Amino-5-(3'-guanidino-phenyl) OH pentanoic acid H-y4 DiHPhe(pNHC(NH)=NH)- (4R)-4-Amino-5-(4'-guanidino-phenyl) OH pentanoic acid H-Y4-DiH2Pal-OH (4R) -4-Amino-5-(pyridine-4'-yl)-pentanoic acid 4 (4R)-4-Amino-5-(pyridine-4'-yl)-pentanoic H-y 4 -DiH4Pal-OH ai acid H-y 4 -DiHPhg-OH (4R)-4-Amino-4-phenyl-butyric acid H-y 4 -DiHCha-OH (4R)-4-Amino-5-cyclohexyl-pentanoic acid H-y 4 -DiHC 4 al-OH (4R)-4-Amino-5-cyclobutyl-pentanoic acid H-y 4 -DiHC 5 al-OH (4R)-4-Amino-5-cyclopentyl-pentanoic acid H-y 4 -DiHN1e-OH (4S)-4-Amino-octanoic acid H-Y4-DiH2Nal-OH (4S) -4-Amino-5-(2'-naphthyl)-pentanoic acid 4 _ (4S)-4-Amino-5-(1'-naphthyl)-pentanoic H-y 4 -DiHiNal-OH ai acid H-y4_DiH4ClPhe-OH (4R)-4-Amino-5-(4'-chlorophenyl) pentanoic acid 4 (4K)-4-Amino-5-(3'-chlorophenyl) H-y 4 -DiH3C1Phe-OH petni aci pentanoic acid 4 (4R)-4-Amino-5-(2'-chlorophenyl) H-y 4 -DiH2C1Phe-OH pnaocai pentanoic acid (4R)-4-Amino-5-(3',4'-dichloro-phenyl) H-y 4 -DiH3,4ClPhe-OH pentanoic acid WO 2011/015241 PCT/EP2009/060168 117 Code Chemical Name (4R)-4-Amino-5-(4'-fluorophenyl) H-y 4 -DiH4FPhe-OH .etni aci pentanoic acid (4R)-4-Amino-5-(3'-flucrophenyl) H-y 4 -DiH3F'Phe-OH petni aci pentanoic acid (4R)-4-Amino-5-(2'-fluorophenyl) H-y 4 --DiH2FPhe-OH petni aci pentanoic acid . (4R)-4-Amino-5-(2'-thienyl)-pentanoic H-y -DiHThi-OH ai acid (4R)-4-Amino-5-(2'- thiazolyl)-pentanoic H-y -DiHTza-OH ai acid (4R)-4-Amino-5-methylsulfoxyl-pentanoic H-y--DiHMso-OH ai acid H-y 4 -DiHAcLys-OH (4S)-8-Acetylamino-4-amino-ocatanoic acid H-y 4 -DiHDpr-OH (4R)-4,5-diamino-pentanoic acid H-yI-DiHA 2 Bu-OH (4R)-4,5-Diamino-hexanoic acid H-y' 1 -DiHDbu-OH (4R)-4,5-Diamion-hexanoic acid H-y'-DiHAib-OH 3-Amino-3,3-dimethyl propionic acid (1'-Amino-cyclopentane-l'-yl)-3-propionic H-y 4 -DiHCyp-OH ai acid 4 (4R)-4-Amino-5-(4'-benzyloxyphenyl) H-y 4 -DiHY(Bzl)-OH petni aci pentanoic acid 4 (4R)-4-Amino-5-(1'-benzylimidazole-4' H-y 4 -DiHH (Bzl) -OH y pnaocai yl)-pentanoic acid H-y 4 -DiHBip-OH (4R)-4-Amino-5-biphenylyl-pentanoic acid H-y 4 -DiHS(Bzl)-OH (4S)-4-Amino-5-(benzyloxy)-pentanoic acid 4 (4R, 5R)-4-Amino-5-benzyloxy-hexanoic H-y 4 -DiHT (Bzl) -OH ai acid H-y4-DiHalloT-OH (4R, 5S)-4-Amino-5-hydroxy-hexanoic acid 4 (4R, 5R)-4-Amino-5-hydroxy-6-methyl H-y 4 -DiHLeu30H-OH h .tni aci heptanoic acid H-y 4 -DiHhAla-OH (4S)-4-Amino-hexanoic acid H-y 4 -DiHhArg-OH (4S)-4-Amino-8-guanidino-octanoic acid H-y4-DiHhCys-OH (4R)-Amino-6-mercapto-hexanoic acid H-y"-DiHhGlu-OH (4S)-4-Amino-ocatanedioic acid H-y 4 -DiHhGln-OH (4S)-4-Amino-7-carbamoyl-heptanoic acid 4 (4S)-4-Amino-6-(imidazole-4'-yl)-hexanoic H-y -DiHhHis-OH ai acid H-y 4 -DiHhIle-OH (4S, 6S)-4-Amino-6-methyl-octanoic acid H-y 4 -DiHhLeu-OH (4S)-4-Amino-7-methyl-ocatanoic acid H-y 4 -DiHhNle-OH (4S)-4-Amino-nonanoic acid H-y 4 -DiHhLys-OH (4S)-4,9-Diamino-nonanoic acid WO 2011/015241 PCT/EP2009/060168 118 Code Chemical Name H-y 4 -DiHhMet-OH (4R)-4-Amino-7-methylthioheptanoic acid H-y 4 -DiHhPhe-OH (4S)-4-Amino-6-phenyl-hexanoic acid H-y 4 -DiHhSer-OH (4R)-4-Amino-6-hydroxy-hexanoic acid H-y"-DiHhThr-OH (4R, 6R)-4-Amino-6-hydroxy-heptanoic acid 4 (4S)-4-Amino-6-(indol-3'-yl)-hexanoi H-y 4 -DiHhTrp-OH cai cacid 4 (4S)-4-Amino-6-(4'-hydroxyphenyl) H-y -DiHhTyr-OH henocai hexanoic acid H-y 4 -DiHhCha-OH (4R)-4-Amino-5-cyclohexyl-pentanoic acid (4R)-4-Amino-5-(4'-benzoylphenyl) pentanoic acid H-y 4 -DiHOctG-OH (4S)-4-Amino-dodecanoic acid H-yz-DiHNle-OH (4S)-4-Amino-octanoic acid H-y 4 -DiHTic-OH (3R)-1',2',3',4'-Tetrahydroisoquinoline 3'-yl-3-propionic acid ,i (1'R)-1',2',3',4'-Tetrahydroisoquinoline l'-yl-3-propionic acid - 4(2'S, 3'aS, 7'aS)-1'-Octahydro-1H-indole 2'-yl-3-propionic acid (2'R, 4'S)-4'-Amino-pyrrolidine-2'-yl-3 H-y -DiH4AmPyrrl-OHacid (2'R, 4'R)-4'-Amino-pyrroiidine-2'-yi-3 H-y 4 -DiH4AmPyrr2-OH poincai propionic acid 4 (2'R, 4'R)-4'-Phenyl-pyrrolidine-2'-yl-3 H-y -DiH4PhePyrrl-OH propionic acid 4 (2'R, 4'S)-4'-Phenyl-pyrrolidine-2'-yl-3 H-y -DiH4PhePyrr2-OH propionic acid H-y I-Di5Pheyrr (2' S, 5'R)-5'-Phenyi-pyrroiidine-2'-yl-3 propionic acid 4_ (2'S, 5'S)-5'-Phenyl-pyrrolidine-2'-yl-3 H-y -DiH5PhePyrr2-OH propionic acid H-y4 _DiHHyp-OH (2'R, 4'S)-4'-Hydroxy-pyrrolidine-2'-yi 2-propionic acid 4 _(2'R, 4'R)-4'-Hydroxy-pyrrolidine-2'-yl 3-propionic acid (2'R, 4'S)-4'-Mercapto-pyrrolidine-2'-yl 3-propionic acid (2'R, 4'R)-4'-Mercapo-pyrrolidine-2'-yl 3-propionic acid H-y 4 -DiHPip-OH (2'S) -Piperidine-2'-y-3-propionic acid H-yL-DiHPro-OH (2'S)-Pyrrolidine-2'-yl-3-propionic acid (AEt)G N- (2-Aminoethyl)glycine (APr)G N-(3-Amino-n-propyl)glycine (ABu)G N- (4-Amino-n-butyl)glycine WO 2011/015241 PCT/EP2009/060168 119 Code Chemical Name (APe)G N-(5-Amino-n-pentyl)glycine (GuEt)G N-(2-Guanidinoethyl)glycine (GuPr)G N- (3-Guanidino-n-propyl)glycine (GuBu)G N- (4-Guanidino-n-butyl)glycine (GuPe)G N- (5-Guanidino-n-pentyl)glycine
(PEG
3 -NH2) G N- [H 2 N- (CH 2 ) 3- (OCH,-CH2) 2-0 (CH 2 ) 31 glycine (Me)G N-Methylglycine (Et)G N-Ethylglycine (Bu)G N-Butylglycine (Pe)G N-Pentylglycine (Ip)G N-Isopropylglycine (2MePr)G N-(2-Methylpropyl)glycine (3MeBu)G N-(3-Methylbutyl)glycine (lMePr)G (1S)-N-(1-Methylpropyl)glycine (2MeBu)G (2S)-N- (2-Methylbutyl)glycine (MthEt)G N-(Methylthioethyl)glycine (MthPr)G N-(Methylthiopropyl)glycine (Ben)G N- (Benzyl)glycine (PhEt)G N-(2-Phenylethyl)glycine (HphMe)G N-([4'-hydroxyphenylimethyl)glycine (HphEt)G N-(2-[4'-hydroxyphenyllethyl)glycine (ImMe)G N- (Imidazol-5-yl-methyl)glycine (ImEt)G N-(2-(Imidazol-5'-yl)ethyl)glycine (InMe)G N-(Indol-2-yl-methyl)glycine (InEt)G N-(2-(Indol-2'-yl)ethyl)glycine (CboMe)G N-(Carboxymethyl)glycine (CboEt)G N-(2-Carboxyethyl)glycine (CboPr)G N-(3-Carboxypropyl)glycine (CbaMe)G N-(Carbamoylmethyl)glycine (CbaEt)G N-(2-Carbamoylethyl)glycine (CbaPr)G N-(3-Carbamoylpropyl)glycine (HyEt)G N-(2-Hydroxyethyl)glycine (HyPr)G (2R)-N-(2-Hydroxypropyl) glycine (Mcet)G N-(2-Mercaptoethyl)glycine NMeAla L-N-Methylalanine NMe DAla D-N-Methylalanine NMeVal L-N-Methvlvaline NMe 2 Val D-N-Methylvaline NMeIle L-N-Methylisoleucine WO 2011/015241 PCT/EP2009/060168 120 Code Chemical Name NMe"Ile D-N-Methylisoleucine NMeLeu L-N-Methylleucine NMe DLeu D-N-Methylleucine NMeNle L-N-Methylnorleucine NMe DNle D-N-Methylnorleucine NMeMet L-N-Methylmethionine NMe DMet D-N-Methylmethionine NMeTyr L-N-Methyltyrosine NMe DTyr D-N-Methyltyrosine NMeHis L-N-Methylhistidine NMe" His D-N-Methylhistidine NMePhe L-N-Methylphenylalanine NMe DPhe D-N-Methylphenylalanine NMeTrp L-N-Methyltryptophane NMe DTrp D-N-Methyltryptophane NMeSer L-N-Methylserine NMe DSer D-N-Methylserine NMeAsp L-N-Methylaspartic acid NMe DAsp D-N-Methylaspartic acid NMeGlu L-N-Methylglutamic acid NMe Glu D-N-Methylglutamic acid NMeLys L-N-Methyllysine NMe DLys D-N-Methyllysine NMeArg L-N-Methylarginine NMe DArg D-N-Methylarginine NMeDab L-N-Methyl-2,4-diamino butyric acid NMeDDab D-N-Methyl-2,4-diamino butyric acid NMeCys L-N-Methylcysteine NMe DCys D-N-Methylcysteine NMeAsn L-N-Methylasparagine NMe DAsn D-N-Methylasparagine NMeGln L-N-Methylglutamine NMe DGln D-N-Methylglutamine NMeThr L-N-Methylthreonine NMe'Thr D-N-Methylthreonine WO 2011/015241 PCT/EP2009/060168 121 Particularly preferred macrocyclic compounds of formula I are the examples: Ex.9, Ex.11, Ex.12, Ex.16, Ex.30, Ex.49, Ex.184, Ex.200, and Ex.213. 5 Synthesis of the Building Blocks Building blocks C used in the synthesis of the macrocyclic compounds of the invention are detailed to the level of fully 10 defined structures shown in Table 19, above and are easily available. Possible synthetic approaches to the modulator building blocks B and, especially, the production of the template building blocks A are described in some detail hereinbelow. 15 Synthesis of the Template Building Blocks A General Transformations Building blocks of type A are based on readily available 20 substances carrying a carboxylic acid group and either a phenolic (Ar/Hetar-OH) or a thiophenolic moiety (Ar/Hetar-SH). The -COOH group may be attached to the same ring as the -OH/ SH group or to an annelated ring which in turn may be aromatic or partially unsaturated. 25 In general phenol derivatives are more abundantly described in the literature than the corresponding thiophenols. However, transformations of phenols into thiophenols are well established. Therefore the phenolic systems can be regarded as precursors towards their thio-analogs. Alternatively 30 thiophenols might be derived from the corresponding aryl halides or diazonium salts. Selected examples of general scope for the transformations Ar/Hetar-X -> Ar/Hetar-SH (X=OH, F, Cl, Br, I, NJ) are introduced below: WO 2011/015241 PCT/EP2009/060168 122 T-I) A sequence of broad applicability is the transformation of a phenol into a thiocarbamate with N,N-dimethylthiocarbamoyl chloride, followed by Newman-Kwart rearrangement and subsequent hydrolysis (A. Gallardo-Godoy et al., J. Med. Chem. 2005, 48, 5 2407-2419; P. Beaulieu et al., Bicrg. Med. Chem. Lett. 2006, 16, 4987-4993; H. Sugiyama et al., Chem. Pharm. Bull. 2007, 55, 613-624; S. Lin et al., Org. Prep. Proced. Int. 2000; 547-556). T-II) The direct transformation of an -OH adjacent to a pyridinic nitrogen (equivalent to the pyridone tautomer) can be 10 accomplished by heating with P 2 S5 (K. Hirai et al., Heterocycles 1994, 38, 277-280). T-III) As an alternative to phenols, halogen-substituted (esp. with F or Cl) aromatic ring systems might serve as precursors. In case the halogen is in a position activated by an electron 15 withdrawing group in ortho- or para-position the -SH moiety or a protected analog can be introduced under mild conditions by nucleophilic aromatic substitution reactions (SNAr) (G. J. Atwell et al., J. Med. Chem. 1994, 37, 371-380) . Especially in the field of heterocyclic compounds, where the electron 20 withdrawing effect is exerted by pyridine-like nitrogen atoms, this type of substitution is often utilized (S. McCombie et al., Heterocycles, 1993, 35, 93-97). T-IV) Similarly, in Sandmeyer-type reactions a diazonium group (-N2J) is replaced (C. Mukherjee, E. Biehl, Heterocycles 2004, 25 63, 2309-2318). T-V) In non-activated positions the substitution of halogen atoms (esp. Br or I) can be accomplished via the corresponding organolithium or Grignard reagents (J. L. Kice, A. G. Kutateladze, J. Org. Chem. 1993, 58, 917-923; P. C. Kearney et 30 al., J. Am. Chem. Soc. 1993, 115, 9907-9919; K.-Y. Jen, M. P. Cava, Tetrahedron Lett. 1982, 23, 2001-2004). Alternatively, transition metal-catalyzed transformations are feasible for this type of reaction, e.g. Cu-catalyzed substitution with benzothioic S-acid (N. Sawada et al., Tetrahedron Lett. 2006, 35 47, 6595-6597), or Pd-catalyzed substitution with KS-Si(i-Pr). followed by desilylation of the thus introduced -SSi(i-Pr) 3 WO 2011/015241 PCT/EP2009/060168 123 group (A. M. Rane et al., Tetrahedron Lett. 1994, 35, 3225 3226). The hydroxyl group attached to the aromatic ring (Ar-OH or 5 Hetar-OH) in turn, if not part of a commercially available substance, can be introduced by various methods: H-I) Analogously to T-III) the hydroxy group or a surrogate can be introduced by an SNAr reaction of halogen atoms, esp. Cl or F, ortho or para to an electron withdrawing substituent (W. 10 Cantrell, Tetrahedron Lett. 2006, 47, 4249-4251) or to a pyridinic nitrogen atom (S. D. Taylor et al., J. Org. Chem. 2006, 71, 9420-9430). H-II) Sandmeyer-type hydroxylations of aromatic amines via intermediate diazonium salts (P. Madsen et al., J. Med. Chem. 15 2002, 45, 5755-5775). H-III) The substitution of halogen atoms (esp. Br and I), not activated for an SNAr, can be achieved by transition metal catalyzed C-0-couplings; predominant are Pd-catalysts (K. W. Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695; B. 20 J. Gallon et al., Angew. Chem., Int. Ed. 2007, 46, 7251-7254), but also others, like Cu-catalysts (J. E. Ellis, S. R. Lenger, Synth. Commun. 1998, 28, 1517-1524), find application. H-IV) Of broad scope is also a two-step process which first transforms halogen atoms (Cl, Br and I) into a boronate and 25 then oxidatively cleaves the carbon-boron bond to the phenol (J. R. Vyvyan et al., J. Org. Chem. 2004, 69, 2461-2468). The carboxylic acid groups of template building blocks A, if not already present in a commercial available building block, 30 can be introduced by standard procedures: C-I) The oxidation of functional groups like hydroxymethyl (
CH
2 -OH) or aldehyde (-C(=O)H) can be achieved under mild conditions (G. V. M. Sharma et al., Synth. Commun. 2000, 30, 397-406; C. Wiles et al., Tetrahedron LeLt. 2006, 47, 5261 35 5264). Also methyl groups on benzene rings can be oxidized; however, as harsh reaction conditions are usually required, its WO 2011/015241 PCT/EP2009/060168 124 applicability is limited. In contrast, the relative acidic methyl groups ortho or para to a pyridine nitrogen can be oxidized under milder conditions; making this the method of choice for many pyridine ring analogs (T. R. Kelly, F. Lang, J. 5 Org. Chem. 1996, 61, 4623-4633). C-II) Halogen atoms can easily be replaced by a carboxyl group or surrogates thereof, e.g. by halogen metal exchange and subsequent carboxylation of the intermediate Grignard or organolithium species (C. G. Screttas, B. R. Steele, J. Org. 10 Chem. 1989, 54, 1013-1017), or by utilizing Mander's reagent (methyl cyanoformate) (A. Lepretre et al., Tetrahedron 2000, 56, 265-274). C-III) In the case that acidified ring positions are to be carboxylated, a viable method is deprotonation with a strong 15 base (usually tert-butyl lithium) followed by carboxylation of the intermediate organolithium species in analogy to C-II). C-IV) Hydrolysis of ester, amide or nitrile groups. The CN group in turn can easily be introduced by treating organic halides with CuCN (Rosenmund-von Braun reaction: C. F. Koelsch, 20 A. G. Whitney, J. Org. Chem., 1941, 6, 795-803). Applied to commercially available starting materials these general transformations offer a tool box for accessing templates A. Further literature example are cited within the 25 category of each embodiment below. Al-A59 Phenyl Derivatives A plethora of hydroxy benzoic acids with diverse substitution patterns are commercially available and can be directly 30 incorporated as template A into the macrocyclic backbone. In several other cases the presence of an optional substituent provides a suitable functionality that can be further extended into more complex high variation substituents by standard methods of organic synthesis and parallel/combinatorial 35 chemistry.
WO 2011/015241 PCT/EP2009/060168 125 Even not so common tetrasubstituted hydroxy benzoic acids (A53 A59) can be built up by procedures in accordance with the general methods mentioned above, for example by carboxylation of pentasubstituted phenol derivatives (K. Sung, R. J. Lagow, J. 5 Mater. Chem. 1996, 6, 917-918; E. Marzi, M. Schlosser, Tetrahedron 2005, 61, 3393-3402; K. C. Nicolaou et al., Angew. Chem., int. Ed. 1999, 38, 3334-3339). Alternative approaches to tetrasubstituted hydroxy benzoic acids involve, for example, the oxidation of benzaldehydes followed by the introduction of 10 substituents into remaining free positions, also feasible to build up polysubstituted benzoic acids from less substituted ones (K. C. Nicolaou et al., Chem. Eur. J. 2000, 6, 3095-3115). A60-A143 Pyridine Derivatives 15 As in the case of the above class of compounds also for pyridine derivatives a very large number of substances are commercially available which can be incorporated into the macrocycle directly, or can easily be transformed into suitable hydroxyl pyridine carboxylic acids by the general 20 methods mentioned above: selected literature examples can be cited for transformations of type C-III (M. Shimano et al. Tetrahedron Lett. 1998, 39; 4363-4366; ibid., Tetrahedron 1998, 54, 12745-12774); for H-II (L. Carpino et al., J. Org. Chem. 2004, 69; 54-61); and for C-I (T. R. Kelly, F. Lang, 25 Tetrahedron Lett. 1995, 36, 5319-5322), or for C-IV (J. L. LaMattina, R. L. Taylor, J. Org. Chem. 1981, 46, 4179-4182). A144- A165 Pyridazine Derivatives In analogy to general transformations which are readily 30 available, suitably substituted methyl pyridazines can be oxidized to the corresponding 3- or 4-carboxylic acids with dichromate (M. Morishita et al., Chem. Pharm. Bull. 1994, 42, 371-372; M. Winn et al., J. Med. Chem. 1993, 36, 2676-2688). Of similarly broad scope is the hydrolysis of the corresponding 35 nitriles under chemical conditions (hydroxide; G. Heinisch, D. Lassnigg, Arch. Pharm. (Weinheim, Ger.) 1987, 320, 1222-1226) WO 2011/015241 PCT/EP2009/060168 126 or under enzymatic conditions (nitrilase from Rhodococcus sp.; N. Klempier et al., Tetrahedron Lett. 1991, 32, 341-344). One possibility to construct the heterocyclic pyridazine core from non-cyclic precursors starts with $-ketoesters which can 5 be subjected to a Staudinger reaction followed by a aza-Wittig cyclization of the intermediate azides (S. V. Galiullina et al., Russ. J. Org. Chem. 2007, 43, 607-614; M. Guillaume et al., Synthesis 1995, 8, 920-922) or directly cyclocondensed with monohydrazone(E. E. Schweizer, K.-J. Lee, J. Org. Chem. 1982, 10 47, 2768-2773). A166- A189 Pyrimidine Derivatives Similarly as with the pyridine derivatives, a large number of suitable building blocks are commercially available and can be 15 directly incorporated into the macrocycle, or they can easily be ransformed into the target compounds by the standard procedures mentioned above, including selected examples for transformations of type C-I (Y. Honma et al., Chem. Pharm. Bull. 1982, 30, 4314-4324); and C-IV (I. V. Oleinik, 0. A. Zagulyaeva, 20 Chem. Heterocycl. Compd. 1993, 29, 427-431). In addition, the pyrimidine core can easily be constructed by cyclocondensation of oxalylic compounds with malonamidine derivative (G. A. Howard et al., J. Chem. Soc. 1944, 476-477) or of malonates with amidine derivatives (M. Otsuka et al., Chem. Pharm. Bull. 25 1985, 33, 515-519). A190- A200 Pyrazine Derivatives Pyrazine carboxylic acids are easily obtained by cyclocondensation of a,-diaminopropionic acid with a,3 30 dicarbonyl derivatives (J. Bostroem et al., Bioorg. Med. Chem. 2007, 15, 4077-4084). Standard protocol examples are for C-I (J. R. Young et al., Bioorg. Med. Chem. Lett. 2000, 10, 1723-1728); for C-III (N. Ple et al., Tetrahedron 1998, 54, 9701-9710); and for H-II (A. P. Krapcho et al., J. Heterocycl. Chem. 1997, 34, 35 27-32). Highly chemosoelective oxidations of type C-I can be WO 2011/015241 PCT/EP2009/060168 127 achived by biotransformations with Pseudomonas putida (A. Kiener, Ang. Chem. 1992, 104, 748-749) A201-A206 Triazine Derivatives 5 A possible route to suitably substituted precursors of difunctional triazines is the cyclocondensation of amidrazones with ap-diketones or a,p-diketoesters (M. Sagi et al., Heterocycles 1990, 30, 1009-1021). Also a,y-diketoesters are described as suitable starting materials, in this case, however, 10 a multi step reaction sequence being required that proceeds via intermediate 4-nitrosopyrazoles (R. Fusco, S. Rossi, Tetrahedron 1958, 3, 209-224). A207-A228 Furan, Thiophene and Pyrrole Derivatives 15 The furans A207 and A208 can be synthesized from suitably substituted 2-formyl- or 2-acetyl-3-oxo-butanoates by bromination followed by cyclization (A. Becker, Helv. Chim. Acta 1949, 32, 1114-1122; R. Richter, Helv. Chim. Acta 1949, 32, 1123-1136). The thiophenes A207 and A208 can be prepared from 20 (substituted) 3-methoxycarbonyl-tetrahydrothiophene-4-one by oxidation (M. R. Banks et al., J. Chem. Res. (M) 1984, 369-389) or by condensation with aldehydes followed by isomerization (R. Jaunin, Helv. Chim. Acta 1980, 63, 1542-1553). The pyrroles A207 and A208 (X = 0) can be obtained from N-protected, 25 suitably substituted 3-amino-acrylates by reaction with (substituted) 2-chloroacetyl chlorides followed by base-induced cyclization (E. Benary, R. Konrad, Chem. Ber. 1923, 56, 44-52). The thioanalogues (X = S) can be synthesized from 3 methoxycarbonyl-furan by dibromination/methanolysis, subsequent 30 reaction with 3-mercapto-propionate and amines, followed by acid-induced cyclization and S-deprotection (F. Eiden, U. Grusdt, Arch. Pharm. 1989, 322, 807-810). The furans A209 and A210 (X = 0) are accessible from (substituted) acetyl(methoxycarbonyl)methylene] 35 triphenylphosphorane by reaction with aldehydes followed by WO 2011/015241 PCT/EP2009/060168 128 ozonolysis and acid-induced isomerization (H. H. Wasserman, G. M. Lee, Tetrahedron Lett. 1994, 35, 9783-9786). The thiophenes A209 and A210 can be prepared from 2-mercaptoacetate and (substituted) acetylene carboxylates (H. Fiesselmann, G. 5 Pfeiffer, Chem. Ber. 1954, 87, 848-856) or from acetyl acetates and 2-mercaptoacetate followed by base-induced cyclization (H. Fiesselmann, F. Thoma, Chem. Ber. 1956, 89, 1907-1912). The pyrroles A209 and A210 can be obtained by condensation of beta-alanine ethyl ester and (substituted) 2,3-dioxo-pent-4 10 enoic esters (H. H. Wasserman et al., Tetrahedron Lett. 1989, 30, 1721-1724) or by reaction of suitably substituted 3-oxo propanoates with glycine esters (A. Treibs, A. Ohorodnik, Liebigs Ann. Chem. 1958, 611, 139-149). The thioanalogues (X = S) can be synthesized from (substituted) pyrrolidine-2 15 carboxylates by subsequent reaction with bistosylsulfur diimide and trimethylphosphite followed by demethylation (J. Hdusler, Monatsh. Chem. 1986, 117, 269-274). The furans of type A211 and A212 can be synthesized from diazomalonates and suitably substituted alkynes in a two-step 20 procedure catalyzed by rhodium(II)-acetate (P. Muller, C. Grdnicher, Helv. Chim. Acta 1993, 76, 521-534) . The thioanalogues (X = S) can be obtained from suitably substituted oxazoles by deprotonation and reaction with dimethyl disulfide, then bromination, lithiation and carboxylation followed by 25 demethylation (S. M. Nolan, T. Cohen, J. Org. Chem. 1981, 46, 2473-2476). The thiophenes A211 and A212 are accessible from (substituted) thiophenes by 5-alkylation and/or 3-carboxylation by deprotonation or lithiation (J. Sic6, J. Am. Chem. Soc. 1953, 75, 3697-3700). The thioanalogues (X = S) can be obtained from 30 (substituted) 2-trimethylsilyloxy-cyclopropanecarboxylates by reaction with carbon disulfide (C. Bruckner, H.-U. Reissig, Liebigs Ann. Chem. 1988, 465-470). The pyrroles A211 and A212 can be prepared from suitably substituted 2-chloroethylidene-malonates by substitution with 35 sodium azide followed by cyclization in the presence of triphenylphosphine (F.-P. Montforts et al., Liebigs Ann. Chem.
WO 2011/015241 PCT/EP2009/060168 129 1990, 1037-1043). The thioanalogues (X = S) can be obtained from suitably substituted 2-oxoethyl-malonates by reaction with isothiocyanates followed by acid-induced cyclization and decarboxylation (J. Fuentes et al., Tetrahedron: Asymm. 1998, 9, 5 2517-2532). Furans of type A213 and A214 are accessible either by 5 lithiation/carboxylation of (substituted) O-protected 2 hydroxy-furans or by 5-bromination of furan-2-carboxylates followed by substitution with methylate and demethylation (D. G. 10 Manly, E. D. Amstutz, J. Org. Chem. 1956, 21, 516-519). The thioanalogues (X = S) can be obtained from (substituted) 1,1 bis(methylthio)prop-l-en-3-one and bromoacetate followed by demethylation (A. Datta et al., Tetrahedron 1989, 45, 7631 7641). The thiophenes A213 and A214 can be prepared analogously 15 as for the compounds A211 and A212 (J. Sic6, J. Am. Chem. Soc. 1953, 75, 3697-3700). The thioanalogues of thiophenes A213 and A214 (X = S) can be synthesized from suitably substituted 2 chloro-thiophenes by 5-carboxylation and subsequent substitution with sodium hydrogensulfide (K. Clarke et al., J. 20 Chem. Soc., Perkin Trans. 1 1980, 1029-1037). The pyrrols A213 and A214 can be obtained from suitably substituted, N-protected glutamate, which is transformed into the didehydro derivative and cyclized in the presence of LiCuMe? (M. M. Paz., F. J. Sardina, J. Org. Chem. 1993, 58, 6990-6995). 25 The thiophenes A215 and A216 (X = S) can be synthesized from (substituted) 3-bromo-thiophenes by a sequence of 3 lithiation/sulfanylation, 2-bromination, 4 lithiation/carboxylation, 2-debromination and 3-demethylation (E. C. Taylor, D. E. Vogel, J. Org. Chem. 1985, 50, 1002-1004). 30 The pyrroles A215 and A216 can be prepared from aminooxoacetate and oxalyl chloride, alcoholysis of the isocyanate, reaction with (3-bromoacetonyl)triphenylphosphonium bromide and N deprotection (J. P. Bazureau et al., Tetrahedron Lett. 1988, 29, 1921-1922), or from (substituted) N-Pfp-protected 3-oxo 35 prolinates by subsequent reaction with base and acid (F.-A. Marcotte, W. D. Lubell, Org. Lett. 2002, 4, 2601-2603). The WO 2011/015241 PCT/EP2009/060168 130 thioanalogues (X = S) can be obtained from suitably substituted pyrrole-2-carboxylates by subsequent reaction with dicyanodisulfane and zinc/acetic acid (A. Berlin et al., J. Chem. Soc, Perkin Trans. 2 1990, 5, 699-704). 5 The furans A217 and A218 may be obtained from (substituted) acetylene carboxylates by reaction with suitably substituted ethoxyvinylidene-tetracarbonyl-ferrocene complexes followed by 0-deprotection (Atiq-ur-Rehman et al., J. Am. Chem. Soc. 1993, 115, 9848-9849). The thioanalogues (X = S) can be synthesized 10 from suitably substituted furan-3-carboxylates by subsequent 5 bromination, reaction with dimethyl disulfide and S deprotection (G. Majetich et al., Tetrahedron Lett. 1994, 35, 4887-4890). The thiophenes A217 and A218 should be accessible from (substituted) formylsuccinates by cyclization in the 15 presence of methanol, hydrogen chloride and hydrogen sulfide, followed by demethylation (S. Mitra et al., J. Chem. Soc. 1939, 1116-1117); or from (substituted) 2,4-dibromothiophene by subsequent reaction with methanol, butyllithium and carbon dioxide followed by demethylation (D. Spinelli et al., J. Chem. 20 Res. (M) 1993, 8, 1873-1890). The pyrroles A217 and A218 (keto tautomer) can be obtained from suitably substituted aminomethylene succinates by base-induced cyclization (C. A. Grob, P. Ankli, Helv. Chim. Acta 1949, 32, 2023-2038). The thioanalogues (X = S) can be synthesized from (substituted) 25 dimethyl (trimethylsilyl)methyl-carbonimidodithioate and (substituted) acetylene carboxylates in the presence of silver fluoride (A. Padwa et al., J. Org. Chem. 1987, 52, 1027-1035). A229-A234 Oxazole, Thiazole and Imidazole derivatives 30 The oxazoles of type A229 can be obtained by reaction of acetyl isocyanates and diazoacetate followed by cyclization (0. Tsuge et al., Tetrahedron 1973, 29, 1983-1990), whereas the thiazoles A229 can be synthesized from bromomalonates and thioamides (F. A. J. Kerdesky et al., J. Med. Chem. 1991, 34, 2158-2165). The 35 imidazoles A229 are accessible by reaction of aminomalonate WO 2011/015241 PCT/EP2009/060168 131 with substituted acetimidates (M. S. Poonian, E. F. Nowoswiat, J. Org. Chem. 1980, 45, 203-208). The oxazoles and thiazoles of type A230 are accessible by cyclizing monoethyl acetamidomalonate in the presence of 5 trifluoroacetic anhydride (to the oxazoles; J. Morgan et al., J. Chem. Soc., Perkin Trans. 1 1997, 5, 613-620), or in the presence of phosphorus pentasulfide (to the thiazoles; A. G. Long, A. Tulley, J. Chem. Soc. 1964, 1190-1192). The thiazoles A230 (with X = S) can be synthesized either from N-thioacetyl 10 glycine by PCl 3 -mediated cyclization followed by subsequent reaction with the Vilsmeyer reagent and hydrosulfide and oxidation of the intermediate aldehyde (to give 2-substituted 5-mercapto-thiazoles; I. Y. Kvitko et al., Chem. Heterocycl. Comp. 1980, 16, 28-31) or from (substituted) 3-bromo-2-oxo 15 propionic acid by reaction with thiourea, 2-deamination via diazotation, 5-bromination, substitution and deprotection (to give 2-unsubstituted 5-mercapto-thiazoles; B. Blank et al., J. Med. Chem. 1977, 20, 572-576). The imidazoles A230 (X = 0) can be obtained from aminomalonate by reaction with 20 trimethylorthoformiate followed by cyclization in the presence of ammonia or amines (R. S. Hosmane, B. B. Lim, Tetrahedron Lett. 1985, 26, 1915-1918) or, for (X = S) by subsequent reaction of 2-amino-2-cyano-acetate with (substituted) trimethylorthoformiate and hydrogen sulfide A. K. Sen, A. K. 25 Mukhopadhyay, Indian J. Chem. B. 1981, 20, 275-278). The oxazoles A231 (X = S) should be obtainable starting from hydroxyacetaldehyde dimer and potassium thiocyanate followed by S-methylation, lithiation/acylation with chloroformiate and demethylation (C. M. Shafer, T. F. Molinski, J. Org. Chem. 1998, 30 63, 551-555). The corresponding thiazoles A231 (X = S) may be synthesized from suitably substituted beta-ketoesters by subsequent reaction with [hydroxy(tosyloxy)iodo]benzene and ammonium dithiocarbamate (P.-F. Zhang, Z.-C. Chen, Synth. Comm. 2001, 31, 415-420). The imidazoles A231 (X = S) can be prepared 35 from N-protected glycine by subsequent reaction with formic acid, methyl formiate and potassium thiocyanate (G. van Lommen WO 2011/015241 PCT/EP2009/060168 132 et al., Bioorg. Med. Chem. Lett. 2005, 15, 497-500), or by C alkylation of N-protected glycine with suitably substituted chloroacetates followed by reaction with potassium thiocyanate (J. Singh et al., Tetrahedron Lett. 1993, 34, 211-214). 5 Oxazoles of type A232 can be prepared from suitably substituted diazoacetates by rhodium-catalyzed reaction with cyanoformiate (G. Shi et al., J. Fluorine Chem. 1991, 52, 149-157). Oxazoles of type A233 can be obtained by heating suitably substituted acetylene carboxylates with diazoacetate followed 10 by demethylation (R. Huisgen, H. Blaschke, Chem. Ber. 1965, 98, 2985-2997).The S-analogues of oxazoles A233 (X = S) are accessible from N-(bismethylthio)glycine esters by reaction with DMF-acetals followed by acid-induced cyclization and demethylation (R. Gompper, U. Heinemann, Angew. Chem. 1981, 93, 15 297-298). The thiazoles A233 (X = 0) can be prepared from suitably substituted cysteine ethyl ester by reaction with diphosgene followed by bromination/elimination (G. Serra et al., Heterocycles 1995, 41, 2701-2711). The oxazoles A234 (X = 0) can be prepared from suitably 20 substituted hydroxyacetonitriles and oxalyl chloride followed by methanolysis of the intermediate and demethylation (K. van Aken, G. Hoornaert, J. Chem. Soc., Chem. Comm. 1992, 12, 895 896). The thiazoles A234 (X = 0) are accessible from suitably substituted 2-mercaptoacetate and cyanoformiate (G. Satzinger, 25 Liebigs Ann. Chem. 1978, 473-511). The corresponding thioanalogues (X = S) can be prepared from (substituted) S methyl 3-oxopropanedithioates and glycine esters followed by cyclization induced by thionyl chloride and demethylation (A. Rahman et al., Synthesis 1984, 250-252). 30 A235-A239 Isoxazole, Isothiazole and Pyrazole Derivatives Isoxazoles A235 can be synthesized from (2-methoxymethylene) malonate substituted in 2-position by reaction with hydroxylamine followed by aqueous HCl (K. Bowden et al., J. 35 Chem. Soc. C 1968, 172-185). The corresponding pyrazoles A235 can be prepared similarly but with hydrazine instead of WO 2011/015241 PCT/EP2009/060168 133 hydroxylamine (T. M. Willson et al., Bioorg. Med. Chem. Lett. 1996, 6, 1047-1050). The isothiazoles A236 can be obtained from suitably substituted O-toluenesulfonyloxyiminoacetates by reaction with 5 thioglycolates (B. Rezessy et al., Tetrahedron Lett. 1992, 33, 6523-6526). The corresponding pyrazoles A236 can be prepared either from suitably substituted 2-oxopropionates by reaction with ethyl hydrazinoacetate followed by methoxide-mediated cyclization (R. N. Comber et al., Carbohyd. Res. 1992, 216, 10 441-452) or from substituted 3-oxopropionates by 2-diazotation followed by cyclization in the presence of sodium hydride (F. J. L. Herrera, C. U. Baelo, Carbohyd. Res. 1985, 143, 161-174). The isoxazoles A237 are accessible by reaction of 4-chloro-3 oxo-butanoates substituted in 4-position with isopentylnitrite 15 (G. Hesse, G. Krehbiel, Chem. Ber. 1955, 88, 130-133). The pyrazoles A237 can be obtained from suitably substituted malonates by reaction with diazoacetate (A. Bertho, H. Niissel, Liebigs Ann. Chem. 1927, 457, 278-307). The pyrazoles of type A238 (keto-isomers) can be synthesized from suitably 20 substituted ketosuccinic acids by reaction with hydrazines in the presence of acetic acid (K. J. Duffy et al., J. Med. Chem. 2001, 44, 3730-3745). Isoxazoles of type A239 can be obtained from 3-substituted 2 bromomaleic acids by esterification followed by reaction with 25 hydroxyurea (C. Bennouna et al., Bull. Soc. Chim. Fr. 1980, 2, 478-480). The isothiazoles A239 can be prepared from 3 substituted 2-aminofurmaramides by subsequent reaction with hydrogen sulfide and bromine followed by hydrolysis of the formed amides (J. Lykkeberg, P. Krogsgaard-Larsen, Acta Chem. 30 Scand. B 1976, 30, 781-785). The corresponding pyrazoles are accessible from (substituted) maleates by reaction with hydrazines followed by oxidation to give the pyrazole ring (G. P. Lahm et al., Bicorg. Med. Chem. Lett. 2007, 17, 6274-6279). 35 A240-A357 Benzofurane, Benzothiophene and Indole derivatives WO 2011/015241 PCT/EP2009/060168 134 The benzothiophenes A240 can be prepared in a multistep sequence starting from suitably substituted 2-hydroxy benzaldehydes, which are transformed into the 3-isopropoxy-2,3 dihydrobenzothiophen-2-ones and then further on functionalized 5 in 2-position and carboxylated in 3-position (A. V. Kalinin et al., J. Org. Chem. 2003, 68, 5992-5999). A possible route to benzofuranes of type A241-A243 involves condensation of suitably substituted cyclohexane-1,3-diones and 3-bromo-2-oxo-propionic acid followed by Pd-catalyzed 10 dehydrogenation (G. Kneen, P. J. Maddocks, Synth. Comm. 1986, 16, 1635-1640). The indoles A244-A247 can be obtained from suitably substituted 2-bromo-3-nitro-benzoates by a Stille coupling to the corresponding 1-ethoxy-styrene followed by a Pd-catalyzed reductive cyclization in the presence of CO and 15 subsequent deprotection of the alcohol and acid (R. W. Clawson et al., Tetrahedron 2006, 62, 10829-10834). The benzofuranes of type A248-A251 can be synthesized from suitably substituted 2,6-dihydroxy-benzoates by reaction with 2-chloroketones (F. H. Curd, A. Robertson, J. Chem. Soc. 1933, 20 714-720) or with chloroacetonitrile in the presence of Lewis acids and HCl followed by acetylation and reductive deoxygenation in 3-position (W. Gruber, K. Horvath, Mh. Chem. 1950, 81, 828-836). The corresponding indoles A250 and A251 should accessible from 6-hydroxy-3-methyl-2-nitro-benzoic acid, 25 which is reacted with dimethylformamide followed by hydrogenation of the nitro group, cyclization, diazotation of the amine and hydroxylation (H. D. Hollis Showalter et al., J. Org. Chem. 1996, 61, 1155-1158). The benzothiophenes A250 and A251 could be obtained from suitably substituted 2-(thiophen-3 30 yl-)acetaldehydes by reaction with propargyl alcohol followed by iodo-cyclization, oxidation of the alcohol to the acid and transformation of the 6-iodo-compound into the alcohol (J. P. Waldo et al., J. Org. Chem. 2008, 73, 6679-6685). The benzothiophenes of type A252-A255 are accessible from 35 suitably substituted methyl 3-methyl-thiophene-2-carboxylate, which is first transformed into the 3-toluenesulfinylmethyl WO 2011/015241 PCT/EP2009/060168 135 compound and then further reacted with suitably substituted acrylates in the presence of base to give the methyl esters of A252-A255 (J. W. Terpstra, A. M. van Leusen, J. Org. Chem. 1986, 51, 230-238). Indoles A252-A255 can be synthesized from methyl 5 2-methoxy-4-methyl-benzoates, which are subsequently brominated in 5-position, nitrated in 3-position, then reacted with dimethylformamide and reduced with Ra/Ni and hydrazine, which triggers a cyclization to the 7-methoxy-6-methoxycarbonyl indoles. These intermediates can then be deprotected to the 10 indoles A252-A255 (P. L. Beaulieu et al., Bioorg. Med. Chem. Lett. 2006, 16, 4987-4993). Possible precursors for benzofuranes A256-A259 and A264-A267 are suitably substituted 2,4-dihydroxy-benzoates which are subjected to alkylation in 4-position with bromoacetaldehyde 15 diethyl acetal followed by cyclization mediated by Amberlyst A15 (M. Dixit et al., Synlett 2006, 10, 1497-1502). Indoles of type A256-A259 (TMS-protected in 4-position, if there is no other substituent) and A264-A267 can be obtained from suitably substituted 5-hydroxy-indoles by formation of the diethyl 20 carbamate followed by anionic Fries rearrangement to the diethyl amide, which is subsequently hydrolyzed with aqueous sodium hydroxide or perchloric acid (E. J. Griffen et al., J. Org. Chem. 1995, 60, 1484-1485). The benzothiophenes of type A260 and A263 should accessible from 4,6-dibromo-benzene-1,3 25 carbaldehyde (substituted in 2- or 5-position) by subsequent substitution of the bromides with methoxide and with 2 mercaptoacetate followed by cyclization, decarboxylation, demethylation and oxidation of the aldehyde to the acid (A. E. Jakobs et al., Tetrahedron 1994, 50, 9315-9324). 30 Benzofuranes of type A268-A271 can be synthesized from the corresponding 4-hydroxy-benzofuranes by carboxylation with carbon dioxide in the presence of methoxide (T. Reichstein, R. Hirt, Helv. Chim. Acta 1933, 16, 121-129) or from suitably substituted 5-carbomethoxy-6-hydroxy-salicylaldehydes by 35 reaction with bromoacetates followed by saponification and cyclization in the presence of acetic anhydride (R. T. Foster, WO 2011/015241 PCT/EP2009/060168 136 A. Robertson, J. Chem. Soc. 1948, 115-116). The preparation of the corresponding benzothiophenes A268-A271 should be possible from suitably substituted 4-oxo-tetrahydrobenzothiophene by acylation with dimethyl carbonate followed by aromatization 5 with DDQ (P. P. Yadav et al., Bioorg. Med. Chem. 2005, 13, 1497-1505). The indoles A268-A271 can be prepared similarly from the 4-oxo-tetrahydroindoles, or alternatively from suitably substituted N-protected 4-amino-salicylic acid via Claisen rearrangement of the O-allyl ether followed by cleavage 10 of the double bond and cyclization (T. Kakigami et al., Chem. Pharm. Bull. 1988, 46, 42-52). Benzofuranes of type A273-A275 can be obtained from 4-0-protected 4-hydroxy-salicylaldehydes by reaction with ethyl diazoacetate in the presence of tetrafluoroboric acid followed by dehydration and deprotection 15 (M. E. Dudley et al., Synthesis 2006, 1711-1714). The benzothiophenes A272-A275 are accessible from 5-bromo benzothiophene (which, in turn, can be prepared from suitably substituted 4-bromo-thiophenols and bromoacetaldehyde diethyl acetal) by Friedel-Crafts acylation, conversion of the methyl 20 ketone into the carboxylate, substitution of the bromide with methoxide and demethylation (S. Mitsumori et al., J. Med. Chem. 2003, 46, 2446-2455). The synthesis of corresponding indoles A272-A275 should be possible by the reaction of suitably substituted para-benzoquinones with substituted 2 25 aminoacrylates in a Nenitzescu reaction (E. A. Steck et al., J. Org. Chem. 1959, 24, 1750-1752) Benzofuranes of type A276-A279 can be obtained from the 3-acetyl-4-hydroxy-benzoates by bromination of the methyl ketone followed by base-induced cyclization to the keto-tautomer of A276-A279 (G. Doria et al., 30 Farmaco 1980, 35, 674-680). The synthesis of 2-substituted benzofuranes A278 can be achieved by alkylation or acylation. The corresponding benzothiophenes A276-A279 may be prepared from suitably substituted 4-fluorobenzoates and thioglycolate by AlCl 3 -induced intramolecular Fridel-Crafts acylation of the 35 intermediate 4-alkoxycarbonyl-phenylsulfanyl acetates (D. L. Gernert et al., Bicorg. Med. Chem. LeLt. 2004, 14, 2759-2764).
WO 2011/015241 PCT/EP2009/060168 137 The benzofuranes and benzothiophenes of type A284-A287 can be synthesized from suitably substituted 3-furaldehydes or 3 formyl-thiophenes by condensation with diethyl succinate followed by cyclization in the presence of acetic anhydride and 5 then base (D. Simoni et al., J. Med. Chem. 2006, 49, 3143-3152). The indoles of type A284 and A287 are accessible from 3 methoxy-4-amino-benzoates by subsequent 5-iodination, Sonogashira coupling with TMS-acetylene and CuI-mediated cyclization followed by demethylation (J. Ezquerra et al., J. 10 Org. Chem. 1996, 61, 5804-5812). Benzofuranes and benzothiophenes of type A288-A291 can be obtained from suitably substituted 2-furaldehydes similarly as described for A284-A287 (D. Simoni et al., J. Med. Chem. 2006, 49, 3143-3152). The indoles A288-A291 can be synthesized similarly from pyrrole-2 15 carbaldehydes and diethyl succinate followed by base-induced cyclization (C. Fuganti, S. Serra, J. Chem. Res. (M) 1998, 10, 2769-2782). The indoles of type A292-A295 can be prepared from N-protected ethyl furo[3,2-blpyrrole-5-carboxylates by decarboxylation with 20 copper chromite in quinoline followed by Diels-Alder reaction with ethyl propiolate and subsequent deprotection (A. Krutosikova, M. Hanes, Collect. Czech. Chem. Comm. 1992, 57, 1487-1494). Benzofuranes of type A296-A299 can be obtained from suitably 25 substituted (p-acetoxyphenoxy)acetyl chlorides by reaction with cyanide followed by cyclization with 1,3-dihydroxy-benzene mediated by zinc(II)-chloride and hydrogen chloride (L. Crombie et al., J. Chem. Soc., Perkin Trans. 1 1987, 2783-2786). The corresponding benzothiophenes A296-A299 can be synthesized from 30 suitably substituted 3-bromothiophenols similarly to the synthesis of A272-A275 (S. Mitsumori et al., J. Med. Chem. 2003, 46, 2446-2455). The access of the indoles A296-A299 can be achieved either from 0-protected 6-hydroxyindoles by acylation in 3-position with trichloroacetyl chloride and methanolysis 35 followed by deprotection (M. Fedouloff et al., Bioorg. Med. Chem. 2001, 9, 2119-2128) or by acylation of suitably WO 2011/015241 PCT/EP2009/060168 138 substituted indoles in 3-position followed by 6-hydroxylation via a Friedel-Crafts acylation/Baeyer-Villiger oxidation sequence (S. Nakatsuka et al., Heterocycles 1987, 26, 1471 1474). 5 The benzofuranes A300-A303 can be obtained from suitably substituted 3-acetyl-furanes by transformation into the silylenol ether followed by Diels-Alder reaction, elimination and dehydrogenation (A. Benitez et al., J. Org. Chem. 1996, 61, 1487-1492). 10 The benzofuranes A304-A307 can be synthesized either from substituted 2-allyl-3-allyloxy-4-methoxy-benzaldehydes by isomerization/metathesis followed by oxidation of the aldehyde and demethylation (W. A. L. van Otterlo et al., Tetrahedron 2005, 61, 7746-7755) or from substituted 2-hydroxy-3-methoxy-6 15 bromo-benzaldehydes by reduction of the alcohol, formation of the phosphonium salt and cyclization in the presence of an acid chloride followed by lithiation/carboxylation and demethylation (K. Hagihara et al., Bicorg. Med. Chem. Lett. 2007, 17, 1616 1621). The corresponding benzothiophenes A304-A307 are 20 accessible from suitably substituted methyl thiophene-2 carboxylates by transformation into the 1-(2'-thienyl)-1,4 dioxobutanes followed by BF 3 -mediated cyclization, 4 carbonylation by Vilsmeyer-Haack reaction, oxidation of the aldehyde and demethylation (S. S. Samanta et al., J. Chem. Soc., 25 Perkin Trans. 1 1997, 3673-3678). The indoles A304-A307 can be obtained either by Diels-Alder reaction of the silylenolate of N-protected 2-acetylpyrrole with propiolate followed by air oxidation (M. Ohno et al., Heterocycles 1991, 32, 1199-1202) or from suitably substituted 30 4-benzyloxy-2-methyl-3-nitro-benzoates (prepared from the 3 methylphenols in a multistep sequence) by subsequent reaction with dimethylformamide and zinc/acetic acid followed by deprotection (M. Tanaka et al., Eur. J. Med. Chem. 1996, 31, 187-198). 35 A358-A372 Pyrrolo[2,3-b]pyridine Derivatives WO 2011/015241 PCT/EP2009/060168 139 The pyrrolopyridines A365 and A366 can be synthesized from 7 azaindole, which is first transformed into N-protected 4 chloro-7-azaindole via the pyridyl-N-oxide (X. Wang et al., J. Org. Chem. 2006, 71, 4021-4023), followed by 5-lithiation and 5 carboxylation, hydrolysis of the chloride and of the ester and N-deprotection (A. L'Heureux et al., Tetrahedron Lett. 2004, 45, 2317-2320). The pyrrolopyridines of type A367 and A368 can be obtained from suitably substituted 4-chloro-3-formyl-pyridines by reaction with azidoacetate followed by a Hemetsberger 10 Knittel reaction(P. J. Roy et al., Synthesis 2005, 2751-2757). The pyrrolopyridines of type A369 and A370 may be accessible from the corresponding substituted 5-chloro-pyrrolopyridine by formylation in a Duff reaction, oxidation to the acid and hydrolysis of the chloride (R. H. Bahekar et al., Bioorg. Med. 15 Chem. 2007, 15, 6782-6795) The synthesis of pyrrolopyridines A371 and A372 may be possible from 4-chloro-7-azaindole by pyridyl-N-oxidation and -methylation followed by substitution with cyanide and hydrolysis of the nitrile and chloride (T. Storz et al., Synthesis 2008, 201-214). 20 A373-A385 Pyrrolo[2,3-c]pyridine Derivatives The pyrrolopyridine A379 might be obtained from suitably substituted 4-iodo-3-nitro-pyridines by a Sonogashira coupling, ethanolysis of the alkyne, reduction of the nitro group and 25 TiCl 4 -mediated cyclization (T. Sakamoto et al., Chem. Pharm. Bull. 1986, 34, 2362-2368). The pyrrolopyridines of type A382 and A383 can be prepared from 2-methoxy-4-iodo-5-aminopyridines by Sonogashira coupling with TMS-acetylene, CuI-mediated cyclization, formylation (and oxidation) in 3-position and 30 demethylation (D. Mazeas et al., Heterocycles 1999, 50, 1065 1080). Pyrrolopyridines of type A384 and A385 are accessible from suitably substituted 4-methoxy-pyrrole-2-carbaldehyde by reductive amination with 3,3-diethoxy-2-amino-propionate, 35 TiCl 4 -mediated cyclization and demethylation (S. K. Singh et al., Heterocycles 1997, 44, 379-392).
WO 2011/015241 PCT/EP2009/060168 140 A386-A398 Pyrrolo[3,2-c]pyridine Derivatives The pyrrolopyridines A387 and A388 could be accessible starting from suitably substituted N-alkylated 2-formyl-pyrroles via the 5 2-pyrrylacryl azides, which are then cyclized to the pyrrolopyridinones. These intermediates are then transformed into the 3-carboxy compounds via the corresponding aldehydes (J. S. New et al., J. Med. Chem. 1989, 32, 1147-1156). The pyrrolopyridines of type A389 and A390 can be obtained from 10 suitably substituted 2-methoxy-3-formyl-pyridines by reaction with azidoacetate followed by a Hemetsberger-Knittel reaction, similarly to the synthesis of A367 and A368 (P. J. Roy et al., Synthesis 2005, 2751-2757). 15 A399-A413 Pyrrolo[3,2-b]pyridine Derivatives Pyrrolopyridines of type A406 and A407 can be obtained from substituted 2-(6-methoxy-3-nitro-2-pyridyl)-acetates by Knoevenagel reaction with formaldehyde followed by Pd-catalyzed cyclization in the presence of hydrogen and CO (B. C. G. 20 Soederberg et al., Synthesis 2008, 6, 903-912). Pyrrolopyridines A410 and A413 can be synthesized from suitably substituted 2-chloro-3-nicotinonitriles by Sonogashira coupling with TMS-acetylene followed by ethanolysis of the alkyne and degradation of the nitrile and finally acid-induced cyclization 25 (T. Sakamoto et al., Chem. Pharm. Bull. 1986, 34, 2362-2368). Alternatively, the synthesis of A410 and A413 can be achieved by reaction of suitably substituted 3-nitro-pyridines with vinylmagnesium bromide (Z. Zhang et al., J. Org. Chem. 2002, 67, 2345-2347). The pyrrolopyridines A408 and A412 can be obtained 30 from 2-alkynyl-3-amino-pyridines by CuI-catalyzed cyclization (A. M. Palmer et al., Bioorg. Med. Chem. 2008, 16, 1511-1530). A414-A449 Benzoxazole, Benzothiazole and Benzoimidazole Derivatives 35 Benzoxazoles A415 and A416 can be prepared starting from N acylated 3-chloro-4-anisidines via benzyne-formation and WO 2011/015241 PCT/EP2009/060168 141 carboxylation (D. R. Reavill, S. K. Richardson, Synth. Comm. 1990, 20, 1423-1436). The corresponding benzimidazoles A415 and A416 are accessible from of 2-amino-3-halo-benzoates by acylation of the amine, nitration in 6-position, alkylation of 5 the amide and cyclization under reductive conditions (K. Kubo et al., J. Med. Chem. 1993, 36, 1772-1784). Benzimidazoles of type A417-A419 can be obtained from 4 acetamido-2-methoxy-benzoates by subsequent chlorination in 5 position and nitration in 3-position, followed by reductive 10 cyclization of the obtained 3-nitro-4-amino-benzoates in the presence of carboxylic acids or formic acid (S. Bolgunas et al., J. Med. Chem. 2006, 49, 4762-4766). This reductive cyclization procedure might also be applicable to the synthesis of other benzimidazoles. Benzimidazoles A420-A422 are accessible from 15 the corresponding 5-methoxy-6-methyl-benzimidazoles by demethylation and oxidation of the methyl group to the carboxylate (B. D. Palmer et al., J. Med. Chem. 1999, 42, 2373 2382). Benzoxazoles of type A423-A425 can be obtained by condensation of substituted 4-methylene-2-oxazolin-5-ones and 20 4-triphenylphosphoranylidene-3-oxobutanoates followed by iodine-mediated aromatization (F. Clerici et al., Tetrahedron 1991, 47, 8907-8916). The synthesis of the corresponding benzimidazoles A423-A425 should be possible starting from 4 amino-2-hydroxy-5-nitrobenzoates via acylation, then reduction 25 of the nitro group and cyclization, as is described for the 2 chloro-benzoates (A. Tanaka et al., Chem. Pharm. Bull. 1994, 42, 560-569). Benzoxazoles of type A426-A428 can be synthesized starting from 2,5-dihydroxybenzoate, which is aminated in 6 position in a multistep sequence, then acylated and cyclized (D. 30 Diez-Martin et al., Tetrahedron 1992, 48, 7899-7939). The benzimidazoles A429-A431 should be accessible from 0 protected 3,4-diamino-2-hydroxy-benzoates, which are mono acylated and then cyclized under acidic conditions (Y. Hirokawa et al., Chem. Pharm. Bull. 2002, 50, 941-959; A. Viger, P. B. 35 Dervan, Bioorg. Med. Chem. 2006, 14, 8539-8549). Benzothiazoles of type A438-A440 can be synthesized by heating suitably WO 2011/015241 PCT/EP2009/060168 142 substituted 4-amino-3-methoxy-benzoates with potassium thiocyanate in the presence of copper(II)-sulfate and subsequent 2-desamination and 3-demethylation (I. A. Ismail et al., J. Org. Chem. 1980, 45, 2243-2246). Benzimidazoles A441 5 A443 can be prepared by a multi-step sequence from 8 aminoquinolines via the corresponding 5,6-dihydro-4H imidazoquinolines (R. C. Elderfield, F. J. Kreysa, J. Am. Chem. Soc. 1948, 70, 44-48). Benzimidazoles A444 and A447 can be obtained by reaction of suitably substituted 3-amino-4-methoxy 10 benzoates with nitriles followed by NaOCl-induced cyclization and subsequent deprotection (J. Reagn et al., Bioorg. Med. Chem. Lett. 1998, 8, 2737-2742). A450-A459 Benzoisoxazole, Benzoisothiazole and Indazole 15 Derivatives Benzoisoxazoles of type A456 and A459 can be synthesized starting from 2,6-dihydroxy-3-formyl-4-methyl-benzoates by reaction with hydroxylamine followed by thermal cyclization (D. H. R. Barton et al., J. Chem. Soc. C 1971, 2166-2174). The 20 application of this method to the synthesis of the other benzisoxazoles (A450-A455, A457 and A458) should be possible. The preparation of indazoles A457 has been described by reaction of 3-amino-2-methoxy-4-methylbenzoate with isoamylnitrite followed by demethylation (S. Bolgunas et al., J. 25 Med. Chem. 2006, 49, 4762-4766); the application to other indazoles (A450-A456 and A458) appears feasible. A460-A515 Naphthalene derivatives A relatively large number of suitably substitued naphthalene 30 derivatives is commercially available. In addition, naphthalenes of type A460-A465 and A496-A499 can be obtained from the corresponding 2-hydroxy-naphthalenes via lithiation and carboxylation (K. Takahashi et al., Tetrahedron 1994, 50, 1327-1340). Alternatively, the demethylation of 2 35 methoxynaphthalene carboxylic acids has been described (Y. Gao et al., J. Med. Chem. 2001, 44, 2869-2878). Higher substituted WO 2011/015241 PCT/EP2009/060168 143 compounds can be prepared in a multistep sequence from suitably substituted 2-bromotoluenes via 2-tetralone-l-carboxylates analogously to the method described by F. C. Goerth et al., Eur. J. Org. Chem. 2000, 2605-2612. 5 Naphthalenes of type A478-A483 and A508-A511 can be prepared either by demethylation of the 3-methoxynaphthalene-1 carboxylates (R. E. Royer et al., J. Med. Chem. 1995, 38, 2427 2432) or by diazotation and subsequent hydrolysis of the corresponding 3-aminonaphthalene-l-carboxylates (K. J. Duffy et 10 al., J. Med. Chem. 2001, 44, 3730-3745). The naphthalenes of type A484-A489 and A504-A507 can be easily built up by a condensation reaction with succinic esters, starting either from suitably substituted benzaldehydes (A. M. El-Abbady et al., J. Org. Chem. 1961, 26, 4871-4873; M. 15 Kitamura et al., Angew. Chem. Int. Ed. 1999, 38, 1229-1232) or from benzophenones (F. G. Baddar et al., J. Chem. Soc. 1955, 1714-1718), depending on the substitution pattern in the desired product. Naphthalene derivatives of type A490-A495 and A512-A515 can be 20 obtained from 2-methoxynaphthalenes by bromination in 4 position, lithiation of the bromide followed by carboxylation and demethylation (J. A. O'Meara et al., J. Med. Chem. 2005, 48, 5580-5588) or from 2-chloro-naphthalene by reaction with phthalic anhydride followed by KOH-induced cleavage (G. Heller, 25 Chem. Ber. 1912, 45, 674-679). A516-A548 Quinoline Derivatives The synthesis of quinolines of type A516-A518 can be accomplished by reaction of suitably substituted isatins with 30 substituted phenacylbromides (H. John, J. Prakt. Chem. 1932, 133, 259-272; E. J. Cragoe et al., J. Org. Chem. 1953, 18, 552 560). Quinolines of type A522-A524 are easily accessible from suitably substituted 2-amino-benzaldehydes via a modified 35 Friedldnder synthesis (D. L. Boger, J.-H. Chen, J. Org. Chem. 1995, 60, 7369-7371). Similarly, quinoline derivatives A527- WO 2011/015241 PCT/EP2009/060168 144 A529 can be obtained from 2-aminobenzaldehydes by condensation with malonic acid (J. Troeger, C. Cohaus, J. Prakt. Chem. 1927, 117, 97-116). Quinolines A525 can be synthesized from the corresponding 2 5 cyanoquinoline-l-oxides by rearrangement (C. Kaneko, S. Yamada, Chem. Pharm. Bull. 1967, 15, 663-669). The quinolines A526 (with a substitution in 4-position) are in principle accessible from substituted 2-aminoacetophenones (with the substitution on the acetyl moiety) by reaction with 3-chloro-3-oxopropionate 10 and subsequent base-induced cyclization (A. Capelli et al., Bioorg. Med. Chem. 2002, 10, 779-802). Quinolines of type A530-A533 can be built up starting from 2 anisidines by reaction with 2-oxosuccinic esters followed by thermal cyclization, demethylation and removal of the 4-hydroxy 15 group via hydrogenation of the corresponding chloride (L. Musajo, M. Minchilli, Chem. Ber. 1941, 74, 1839-1843) For the synthesis of quinolines of type A543-A545 the condensation of suitably substituted isatins with malonic acid has been described (e.g. W. Borsche, W. Jacobs, Chem. Ber. 1914, 20 47, 354-363; J. A. Aeschlimann, J. Chem. Soc. 1926, 2902-2911). A549-A564 Isoguinoline Derivatives Isoquinolines of type A549-A553 with the carboxylate in the 1 position can be prepared from suitably substituted 25 benzaldehydes, which are transformed into the aminoethanes followed by reaction with oxalic ester aldehyde or acid chloride, cvclization, oxidative aromatization and finally saponification (M. Keizo et al., Chem. Pharm. Bull. 1982, 30, 4170-4174; S. Naoki et al., Chem. Pharm. Bull. 1989, 37, 1493 30 1499). Isoquinoline-3-carboxylates (A554-A556) are accessible from hydroxylated phenylalanines via a Bischler-Napieralski reaction followed by oxidative aromatization, or alternatively from suitably substituted 2-methyl benzaldehydes, which are reacted 35 with methyl azidoacetate and then cyclized under thermal conditions followed by aromatization (Y. Fukuda et al., J. Med.
WO 2011/015241 PCT/EP2009/060168 145 Chem. 1999, 42, 1448-1458; T. R. Burke et al., Heterocycles 1992, 34, 757-764). Compounds of type A557 and A558 can be built up by reaction between suitably substituted 2-aminobenzoic acids and 5-chloro 5 3-carboxy-1,2,4-pyrazines in the presence of amylnitrite followed by hydrolysis (A. M. d'A. Rocha Gonsalves, T. M. V. D. Pinho e Melo, Tetrahedron 1992, 48, 6821-6826), whereas isoquinolines A559 and A560 can be prepared by reaction of 2 formylbenzoic acids with 2-thioxothiazolidin-4-one followed by 10 cyclization and transformation of the isothiochromenone into the isoquinoline with ethanolic ammonia (D. J. Dijksman, G. T. Newbold, J. Chem. Soc. 1951, 1213-1217). The access to isoquinolines A561 and A562 might be possible by transformation of suitably substituted isquinolines into the 15 corresponding Reissert compounds, nitration in 4-position and hydrolysis of the nitrile (M. Sugiura et al., Chem. Pharm. Bull. 1992, 40, 2262-2266) followed by hydrogenation of the nitro group, diazotation of the amine and transformation into the hydroxyl group. 20 Isoquinolines of type A563 and A564 are accessible from suitably substituted (2-methoxycarbonyl-phenyl-)acetic acids via reaction with methyl formiate followed by cyclization of the formed enol and amination of the isochromenone (H. E. Ungnade et al., J. Org. Chem. 1945, 10, 533-536). 25 A565-A577 Quinazoline Derivatives The most general routes to quinazolines use appropriately substituted phenyl derivatives onto which the pyrimido ring is cyclized, e.g. the cyclocondensation of 2-amino benzamides with 30 oxalates (M. Suesse et al., Helv. Chim. Acta 1986, 69, 1017 1024), of ortho-carbonyl substituted phenyl oxalamic acid esters with ammonium formate (S. Ferrini et al., Org. Lett. 2007, 9, 69-72), or of 2-amino benzonitriles with carbonylformimidate or chloroformamidine (A. McKillop et al., 35 Tetrahedron Lett. 1982, 23, 3357-3360; N. Harris et al., J. Med. Chem. 1990, 33, 434-444), or of ortho-oxalyl anilides with WO 2011/015241 PCT/EP2009/060168 146 ammonia (M. T. Bogert, F. P. Nabenhauer, J. Am. Chem. Soc. 1924, 46, 1702-1707). A578-A587 Quinoxaline Derivatives 5 The synthesis of quinoxalines of types A578-581 via their 2 carbaldehydes is well-described (E. Lippmann et al., Zeitschr. Chem. 1990, 30, 251-252). The other representatives of these groups A582-587 are available by cyclocondensation of P dicarbonyl derivatives or -keto-esters with appropriately 10 substituted ortho-phenylendiamines (S. Grivas et al., Acta Chem. Scand. 1993, 47, 521-528; A. Zychilinski, I. Ugi, Heterocycles 1998, 49, 29-32; D. Zhou et al., Bioorg. Med. Chem. 2008, 16, 6707-6723). Unique to the quinoxaline is the possibility to introduce a carboxyl group in the 2-position by enzyme catalyst 15 biotransformation applying Arthrobacter nicotianae (T. Yoshida et al., Biosci. Biotech. Biochem. 2002, 66, 2388-2394). A588-A601 Pyrido[5,4-dlpyrimidine Derivatives The bicyclic core can be accessed by annelating suitably 20 substituted pyridines by cyclocondensation reactions. Feasible starting materials include pyridine-2,3-dicarboxylic acids (A. Tikad et al., Synlett 2006, 12, 1938-1942), 3-aminopyridine-2 carboxylates (M. Hayakawa et al., Bioorg. Med. Chem. 2006, 14, 6847-6858) or 3-aminopyridine-2-nitriles (J. B. Smaill et al., 25 J. Med. Chem. 2000, 43, 1380-1397). A602-A608 Pyrimido[5,4-d]pyrimidine Derivatives Access to the pyrimidopyrimidine group of templates might be achieved via the literature-known 4,6-dichloro derivative (G. 30 Rewcastle et al., J. Med. Chem. 1997, 40; 12, 1820-1826) or the corresponding 2,4,6,8-tetrachloro derivative (J. Northen et al., J. Chem. Soc., Perkin Trans. 1, 2002, 108-115) using the general methods described above and separation of the expected isomeric mixtures. 35 WO 2011/015241 PCT/EP2009/060168 147 A609-A618 Tetraline Derivatives A large number of reaction sequences that lead to tetraline derivatives involve an intramolceular Friedel-Crafts acylation as a key step, and the prerequisite cyclization precusors can 5 be elaborated from phenylacetonitriles, 2-phenyl malonates (R. S. Natekar, S. D. Samant, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2002, 41, 187-190; L. Gong, H. Parnes, J. Labelled Compd. Radiopharm. 1996, 38, 425-434). Alternatively, the intramolecular cyclization can be achieved by a Buchner 10 Reaction (A. Cheung et al., Bloorg. Med. Chem. Lett. 2003, 13, 133-138). Subsequently, the carbonyl groups of the thus obtained 1- or 2- tetralones can easily be converted into carboxyl moieties (M. Meyer et al., J. Med. Chem. 1997, 40, 104-1062; F. Berardi et al., J. Med. Chem. 2004, 47, 2308-2317). 15 A619-A626 Indane Derivatives Indane derivatives of types A619-A623 with a carboxyl group in the 1-position are accessible from appropriately substituted and easily available 3-cyano-indenes by hydrogenation to the 20 indane core followed by hydrolysis to the carboxyxlic acid moiety (T. McLean et al., J. Med. Chem. 2006, 49, 4269 - 4274). Also indan-1-ones can be transferred into indane-l-caboxylic acids, for example via oxiranes (D.-I. Kato et al., J. Org. Chem. 2003, 68, 7234 - 7242), or in a Corey-Seebach-type 25 reaction via 1,3-dithianes (Y.-P. Pang et al., J. Org. Chem. 1991, 56, 4499 - 4508). Indane derivatives of types A624-A626 with a carboxyl group in 2-position can be obtained from readily accessible, suitably substituted indan-1-ones by treatment of the corresponding 30 enolate with a dimethyl carbonate, hydrogenation of the carbonyl group and hydrolysis of the introduced ester group (T. Tanaka et al., Chem. Pharm. Bull. 1994, 42, 1756 - 1759; U. Hacksell et al. J. Med. Chem. 1981, 24, 429 - 434). Alternatively the indane ring system can be built up starting 35 from ortho-xylenes by NBS bromination of both methyl residues, alkylation-spirocyclization with the enolate of barbituric acid WO 2011/015241 PCT/EP2009/060168 148 and finally decarboxylative ring cleavage to indane-2-caboxylic acids (G. A. Kraus et al., J. Org. Chem. 2002, 67, 5857 - 5859). Synthesis of Building Blocks for the Modulators B 5 The Modulator moieties B of the macrocycle I are derived from appropriately substituted aminoalcohols, wherein the amino and alcohol group, which contribute to the ring connectivity, are separated from by 2-4 C-atoms. If not already present in a commercial building block, the 10 substituent R 3 can be introduced by standard nucleophilic addition of organo metallic reagents to carbonyl or carboxyl derivatives. For B18-B21, carrying no additional C-substituent on their ring system, such precursors are commercially available. Similarly, in the case of B9, B10, B16 and B17 the 15 diversification of the substituent pattern can be easily achieved by standard transformations of the commercial analogs with free amine functionalities (i.e. -NH 2 -+ -NR'I 2 in the case of B9 and -NH -> -NR" for B10, B16 and B17) 20 B1 Aziridine Derivatives Usually, the access to hydroxymethyl aziridines relies on reaction sequences involving the construction of the aziridine ring. The starting materials with the broadest applicability are $-ketoesters: Transformation into the f-hyroxyimino analog, 25 intramolecular cyclisation to the aziridine ring and reduction of the ester to the alcohol group leads to building blocks of type B1 (e.g. T. Sakai et al., J. Org. Chem. 2005, 70, 1369 1375) . An alternative approach uses a,-dihaloester which are converted into substances of type B1 via aziridination with 30 ammonia and reduction of the ester group (P. Davoli et al., Tetrahedron 2001, 57, 1801 - 1812). B2-B3 Azetidine Derivatives The standard approaches to hydroxymethyl azetidines comprises 35 subjecting easily accessible 0-protected glycidols to, WO 2011/015241 PCT/EP2009/060168 149 successively, an epoxide-ring opening with azide, transformation of the OH group of the thus obtained alcohol into a suitable leaving group (e.g. tosylate or sulfate), reduction of the azide to an amine and concomitant 5 intramolceular cyclization (F. Hosono et al., Tetrahedron 1994, 50, 13335-13346; D.-G. Liu, G.-Q. Lin, Tetrahedron Lett. 1999, 40, 337-340). B4-B8 Pyrrolidine Derivatives and B11-B15 Piperidine 10 Derivatives The synthetic approaches to the pyrrolidine and piperidine classes of building blocks B rely on the same strategies and are therefore discussed together. Intramolecular cyclization reactions are the predominant routes applicable to a broad 15 number of diversely substituted substrates: Amines carrying a residue with a leaving group in the co-position lead directly to the desired saturated ring systems by an intramoleular nulceophilic substitution (G. Ceulemans et al., Tetrahedron 1997, 53, 14957-14974; S. H. Kang, D. H. Ryu, Tetrahedron Lett. 20 1997, 38, 607-610; J. L. Ruano et al., Synthesis 2006, 687-691). Also N-haloamines can be directly transformed to the desired compounds by the Hofmann-Ldffler-Freytag reaction (M. E. Wolff, Chem. Rev. 1963, 63, 55-64). Alternatively amines carrying two substituents, each with an alkene or alkyne bond, can be 25 subjected to a ring closing metathesis (RCM) reaction (Y. Coquerel, J. Rodriguez, Eur. J. Org. Chem. 2008, 1125-1132) and subsequent reduction of the thus obtained partially unsaturated ring to the saturated heterocycle. Also the reduction of the corresponding aromatic five- and six 30 membered heterocycles to their saturated analogs is described in the literature. However, due to the large number of commercially available pyridines this approach is mainly applied to the synthesis of the piperidine system (J. Bolos et al., J. Heterocycl. Chem. 1994, 31, 1493-1496; A. Solladie- WO 2011/015241 PCT/EP2009/060168 150 Cavallo et al., Tetrahedron Lett. 2003, 44, 8501-8504; R. Naef et al., J. Agric. Food Chem. 2005, 53, 9161-9164). Procedures for the synthesis of libraries of macrocyclic 5 compounds of general structure I are described below but it will immediately apparent to those skilled in the art how these procedures have to be modified if it is intended to synthesize one single macrocyclic compound of formula I. 10 The macrocyclic compounds of the invention are obtained by cyclization of suitable linear precursors which are derived from optionally substituted hydroxyaryl, hydroxyheteroaryl, mercaptoaryl, or mercaptoheteroaryl carboxylic acids A ("template", a), substituted amino alcohols B ("modulator", b) 15 and one to three building blocks of type C forming the "bridge" C. Variable substituents are introduced by pre- or postcyclative derivatization of one or more orthogonally protected attachment 20 points (e.g. amino groups, carboxyl groups, hydroxyl groups) on building blocks B and C, and optionally A. Variable R-groups may also be introduced as side chain motifs in building blocks C. 25 The macrocyclic products of the invention can be prepared either in solution or on a solid support. In accordance with the present invention, the ring closure reaction is, in principle, possible between any of the building 30 blocks. Macrocycles of general structure I with building block c forming the bridge c are obtained by either a) macrolactamisation between c and B; or 35 b) macrolactamisation between A and c; or WO 2011/015241 PCT/EP2009/060168 151 c) aryl- or thioaryl ether formation between A and B; or, alternatively, d) Ring closure metathesis reaction within building blocks of type C is also possible. 5 Macrocycles of structure I with orthogonally protected exocyclic functional groups (attachment points for derivatization) are prepared in solution by a process which 10 comprises: a') condensation of an appropriately protected hydroxy- or mercapto-aryl/heteroaryl carboxylic acid PG-A-OH and a suitably C-terminal- and appropriately side-chain-protected building block H-cl-OPG to form 15 PG-A-cl-OPG; b2) if required release of the aryl/heteroaryl (phenolic) OH group or mercapto group, respectively; c2) aryl/heteroaryl ether or thioether formation with a suitably N-protected amino alcohol HO-B-PG leading to the fully 20 protected linear cyclization precursor PG-B-A-cl-OPG; d2) cleavage of the "main chain" protective groups (PG) affording the free amino acid H-B-A-cl-OH (still carrying appropriately protected side chain functional groups); followed by either 25 e') intramolecular amide coupling affording protected macrocycles of general formula I (yielding cyclo-(B-A-cl) still carrying orthogonally protected side chain functional groups); or f') N-reprotection of the product obtained in step d'); 30 g') coupling of a suitably C-protected amino acid H-c2-OPG; h2) cleavage of the "main chain" protective groups affording the free amino acid H-B-A-cl-c2-OH (still carrying appropriately protected side chain functional groups); i]) intramolecular amide coupling affording the protected 35 macrocycles of general formula I (yielding cyclo-(B-A-cl-c2); WO 2011/015241 PCT/EP2009/060168 152 still carrying orthogonally protected side chain functional groups); or j') N-protection of the product obtained in step d'); k2) coupling of a suitably C-protected amino acid H-c2-OPG 5 11) cleavage of the C-terminal protective group or cleavage of N- and C-terminal main chain protective groups and reprotection of the N-terminus; M2) coupling of a suitably C-protected amino acid H-c3-OPG; n2) release of the "main chain" protective groups affording the 10 free amino acid H-B-A-cl-c2-c3-OH (still carrying protected side chain functional groups); and 02) intramolecular amide coupling affording the protected macrocycles of general formula I (yielding cyclo-(B-A-cl-c2-c3), still carrying protected side chain functional groups). 15 The appropriately protected, preferably acyloxy- or acylmercapto-, most preferably acetyloxy- or acetylmercapto substituted aryl/heteroaryl carboxylic acid (PG'-A-OH) is converted into the corresponding acid chloride and condensed 20 with a suitably protected amino acid ester H-cl-OPG 2 in the presence of an auxiliary base (e.g i-PrNEt, Et 3 N, pyridine, collidine) and in solvents like CH 2 Cl2, CHCl 3 , THF to afford after deacylation (preferably by aminolysis) the hydroxyl or mercapto aryl/heteroaryl amide H-A-cl-OPG 2 . 25 The aminolysis is advantageously carried out with a dialkylaminoalkyl amine in solvents like THF at 0-25 0 C. Acyl amine side products formed in the course of the reaction can thus be removed by extraction with acidic aqueous solutions. 30 Alternatively, the acyloxy or acylmercapto aryl/heteroaryl carboxylic acid (PG-A-OH) can be coupled in the presence of a coupling reagent (such as benzotriazol derivatives like HBTU, HCTU, PyBOP, or their aza analogs such as HATU, or 35 carbodiimides such as EDC) to the amino acid ester H-cl-OPG 2 to WO 2011/015241 PCT/EP2009/060168 153 afford, after deacylation, the phenol or thiophenol H-A-cl-OPG 2 . The phenol H-A-cl-OPG 2 can also be directly obtained from the 5 hydroxyaryl/heteroaryl carboxylic acid H-A-OH and the amino acid ester H-cl-OPG 2 in the presence of a coupling reagent. Alkylation of the phenol or thiophenol H-A-C 1
-OPG
2 with a suitably N-protected amino alcohol HO-B-PG 3 to give the ether 10 or thioether PG -B-A-c1-OPG 2 is achieved using azodicarboxylic acid derivatives such as DEAD, DIAD or ADDP in the presence of trialkyl or triaryl phosphines in solvents like benzene, toluene, CH2Cl 2 , CHCl 3 or THE at 0 0 C to room temperature. As a 15 variation, the reaction can be induced with CMBP in toluene at temperatures ranging from 20 - 110 C. As an alternative, the alcohol HO-B-PG 3 can be converted into a corresponding sulfonates (such as for example the mesylate, 20 tosylate, triflate) or a corresponding halide (such as chloride, bromide and iodide) and subsequently be treated with the phenol or thiophenol H-A-cl-OPG in the presence of an auxiliary base such as for example NaH or KCO3 in solvents like DMF, DMSO, NMP, HMPA, THF, 25 to give the ether or thioether PG -B-A-c1-OPG'. Simultaneous or stepwise cleavage of the main chain protective groups provides the linear amino acid cyclization precursor H B-A-cl-OH. Alloc (for PG 3 ) and allylester groups (for PG 2 ) are 30 preferred as protecting groups and best cleaved simultaneously mediated by palladium catalysts, e.g. Pd(PPh 3
)
4 , in the presence of 1,3-dimethyl barbituric acid in solvents like
CH
2 Clz or EtOAc or mixtures thereof.
WO 2011/015241 PCT/EP2009/060168 154 Macrolactamization occurs upon treatment of the cyclization precursor H-B-A-cl-OH - if required in the presence of an auxiliary base such as i-Pr 2 NEt - with coupling reagents like T3P or FDPP in 5 solvents like CH2Cl2 or DMF under high dilution conditions and at temperatures ranging from 20 to 100'C to yield cyclo-(B-A c1). For examples of macrolactamizations mediated by FDPP see J. Dudash, J. Jiang, S.C. Mayer, M.M. Joulli6, Synth. Commun. 1993, 10 23 (3), 349 - 356; R. Samy, H.Y. Kim, M. Brady, and P.L. Toogood, J. Org. Chem. 1999, 64, 2711 - 2728. It is well known that many other coupling reagents have been used in such head to tail cyclizations to prepare macrolactams, 15 and such other coupling reagents might, alternatively, be engaged in the above mentioned reactions. Examples include benzotriazole derivatives such as HBTU, HCTU, PyBOP and their aza analogs such as HATU, as well as DPPA, and carbodiimides like EDC, DIPCDI; for examples see P. Li, P.P. Roller, Current 20 Topics in Mecicinal Chemistry 2002, 2, 325 - 341; D.L. Boger, S. Miyazaki, S.H. Kim, J. H. Wu, S.L. Castle, 0. Loiseleur, and Q. Jin, J. Am. Chem. Soc. 1999, 121, 10004 - 10011). Another option to obtain macrolactams comprises the 25 intramolecular reaction of an active ester with an in situ released amino group (carbamate deprotection, azide reduction) as demonstrated for example in the synthesis of peptide alkaloids and vancomycin model systems (U. Schmidt, A. Lieberknecht, H. Griesser, J. Talbiersky, J. Org. Chem. 1982, 30 47, 3261 - 3264; K.C. Nicolaou, J.M. Ramanjulu, S. Natarajan, S. Brdse, H. Li, C.N.C. Boddy, F. Rtibsam, Chem. Commun. 1997, 1899 - 1900.) N-reprotection of H-B-A-cl-OH can be achieved applying standard 35 amino acid protection protocols. Chloroformates or N-hydroxy- WO 2011/015241 PCT/EP2009/060168 155 succinimidyl carbonates in solvents like dioxane, if required in the presence of a base such as aqueous K 2
CO
3 solution, react to give the N-protected amino acid PG 3 -B-A-cl-OH. 5 Coupling of an additional amino acid can be effected applying classical peptide coupling conditions. Building blocks c1 - c3 can be derived from tri-functionalized 10 aminoacids (e.g. derivatives of Dap, Dab, Orn, Lys, Asp, Glu), main chain- or side chain- functional groups of which may be part of the macrocyclic scaffold. Non proteinogenic tri-functionalized amino acid building blocks can be obtained by various synthetic methods, among others 15 formal alkylation of the side chain hydroxyl group of Ser, HomoSer, Thr or derivation of the mercapto group of Cys, HomoCys with Q-haloalkyl carboxylic esters. An alternative route for synthesizing macrocyclic compounds of 20 the invention comprises a2) synthesis of the H-A-cl-OPG 2 fragment as described above; b 2 ) N-acylation of the aminoalcohol HO-B-H with a suitably N terminal protected amino acid PG 4 -c2-OH to afford the amidoalcohol PG 4 -c2-B-OH; 25 c 2 ) aryl or thioaryl ether synthesis starting from H-A-cl-OPG 2 and
PG
4 -c2-B-OH, applying conditions as described above; d') release of the "main chain" protective groups to give the cyclization precursor H-c2-B-A-cl-OH; and 30 e 2 ) macrolactamization as described above, affording the protected macrocycles of general formula I (cyclo-(c2-B-A-cl), side chain functional groups still carrying orthogonal protective groups).
WO 2011/015241 PCT/EP2009/060168 156 The fragment PG 4 -c3-B-OH can be prepared by N-Acylation of the amino alcohol HO-B-H with suitable N-terminal protected amino acid PG4-C3-OH. N-deprotection and coupling to an appropriately N-terminal protected amino acid PG 5 -c2-OH affords the alcohol 5 PG 5 -c2-c3-B-OH which can then be converted - by effecting steps corresponding to c 2 ), d2) and e 2 ) - into the protected macrocycles of general formula I (cyclo(c2-c3-B-A-c1), side chain functional groups still carrying orthogonal protective groups). 10 As a further alternative, cyclization can be obtained by ring closing metathesis. The orthogonally protected macrocycles of general structure I are synthesized applying a process which comprises 15 a 3 ) coupling of an optionally substituted alkenyl amine containing building block cl(alkenyl) of type C to the acyloxy or hydroxy or acylmercapto aryl/heteroaryl carboxylic acid PG A-OH; b3) if required release of the aryl/heteroaryl (phenolic) OH 20 group or mercapto group, respectively; c3) N-acylation of the aminoalcohol HO-B-H with an optionally suitably substituted alkenyl carboxylic acid PG 6 -c2 (alkenyl) -OH to afford the amido alcohol PG-c2 (alkenyl)-B-OH; d3) aryl or thioaryl ether formation as described above to 25 yield the cyclization precursor PG-c2 (alkenyl)-B-A c1 (alkenyl); e3) ring closure metathesis; and f3) optional hydrogenation of the newly generated olefinic double bond of the metathesis product of step e3). 30 Ring closure metathesis to form macrocyclic compounds from olefinic precursors is well known (for examples see A. Ftirstner, 0. Guth, A. Duffels, G. Seidel, M. Liebl, B. Gabor, and R. Mynott, Chem. Eur. J. 2001, 7 (22), 4811 - 4820). 35 WO 2011/015241 PCT/EP2009/060168 157 Ring closure metathesis of PG 6 -c2 (alkenyl)-B-A-cl(alkenyl) is conveniently performed in suitable solvents, like CH 2 C1 2 or toluene, at 20 to 100'C in the presence of indenylidene ruthenium complexes including dichloro-(3-phenyl-lH-inden-l 5 ylidene)bis(tricyclohexylphosphine)-ruthenium (II), [1,3 Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(3 phenyl-lH-inden-1-ylidene(tricyclohexylphosphine)-ruthenium(II), [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro-(3-phenyl-lH-inden-1-ylidene) (pyridyl)ruthenium(II) 10 (see S. Monsaert, R. Drozdzak, V. Dragutan, I. Dragutan, and F. Verpoort, Eur. J. Inorg. Chem. 2008, 432 - 440 and references therein). Derivatization of the macrocyclic core structures with variable 15 R-groups can be effected as described hereinbelow. Orthogonally protected attachment points (e.g. exocyclic amino groups, carboxyl groups, hydroxyl groups) allow stepwise deprotection and derivatization. 20 The reactions can be carried out in a parallel fashion to generate libraries of final products. The following general process can be applied: a/) Cleavage of the first protective group; 25 b 4 ) derivatization of the free functional group; c4) cleavage of the second protective group, and d4) derivatiszation or the free functional group. Amine protecting groups such as preferably Boc, Cbz, Teoc, 30 Alloc, Fmoc are removed applying standard conditions, cf. T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1999; P.J. Koncienski, Protecting Groups, 3rd edition, Georg Thieme Verlag, 2005.
WO 2011/015241 PCT/EP2009/060168 158 Carboxylic acid protecting groups such as tert.butyl, benzyl, allyl, methyl are removed applying standard conditions. Alcohol protecting groups such as tert.butyl, benzyl, allyl, 5 acetyl, benzoyl, pivaloyl are removed applying standard conditions. Attachment point amino groups can be converted into amides by reaction with carbonyl chlorides, carboxylic acid anhydrides 10 active esters or by treatment with carboxylic acids in the presence of soluble or polymer-supported coupling reagents such as for example HATU, T3P or polymer-supported carbodiimides. Reductive alkylation of the attachment point amino groups or 15 their reaction with alkyl halides, alkylsulfonates or Michael acceptors affords higher alkylated amines. The reaction of attachment point amino groups with isocyanates or equivalents like carbamoyl chlorides or hydoxysuccinimidyl 20 esters affords ureas. The reaction of attachment point amino groups with isothiocyanates provides thioureas. 25 The reaction of attachment point amino groups with chloroformates or equivalents such as hydroxysuccinimidyl carbonates affords carbamates. The reaction of attachment point amino groups with sulfonyl 30 chlorides yields sulfonamides. The reaction of attachment point amino groups with suitably activated aromatic or heteroaromatic halides or sulfonates - in the presence of auxiliary base and if required a Pd catalyst WO 2011/015241 PCT/EP2009/060168 159 (e.g. Buchwald couplings) - affords the corresponding N-aryl or N-heteroaryl derivatives. Attachment point carboxyl groups are converted into amides 5 using amines and coupling reagents. Attachment point alcoholic hydroxyl groups can be alkylated with alkyl halides or alkylsulfonates to give alkylethers. Their reaction with phenols in the presence of azodicarboxylic 10 acid derivatives and triaryl or trialkyl phosphines as well as their reaction with suitably activated aryl or heteroaryl halides or sulfonates affords aryl or heteroaryl ethers. Attachment point secondary alcoholic hydroxyl groups can be 15 oxidized to the corresponding ketones which in turn may be submitted to a reductive amination using amines and a suitable reducing agent. Attachment point alcoholic hydroxyl groups can be converted into esters. 20 Appropriate macrocyclic compounds of general formula I with one or more (orthogonally) protected exocyclic functional groups and a free primary amino group can be converted into fully derivatized products on solid support. 25 A process, which allows an efficient parallel array derivatization, comprises a5) attachment of the macrocyclic amine to an appropriately functionalized solid support in a reductive amination step; b5) acylation, carbamoylation, oxycarbonylation or 30 sulfonylation of the secondary amine thus obtained in step a5); c5) Removal of the protective group of the next attachment point; d 5 ) Derivatisation of the second free functional group whereby WO 2011/015241 PCT/EP2009/060168 160 amino groups can be converted into amides, ureas, thioureas carbamates, or sulfonamides, or can be alkylated; and carboxylic acids can be converted into amides; e 5) repetition of steps c 5 ) and d) if an additional 5 derivatisation site is available; and f 5 ) Release of the final product from solid support. In priniciple a macrocyclic carbocylic acid can be coupled to polymer-supported amines and be converted into final products 10 by effecting steps corresponding c 5 ) to f 5 ). The functionalized solid support is a derivative of polystyrene cross- linked with preferably 1-5% divinylbenzene, of polystyrene coated with polyethyleneglycol (TentagelR), and of 15 polyacrylamid resins (see D. Obrecht, J.-M. Villalgordo, "Solid-Supported Combinatorial and Parallel Synthesis of Small Molecular-Weight Compound Libraries", Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998). 20 The solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures. 25 For the purposes of the present invention, linkers are used which are designed to release an N-acyl derivative (amide, urea, carbamate) or a sulfonamide under acidic conditions. Such linkers have been applied in the backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal modified and 30 cyclic peptides (K.J. Jensen, J. Alsina, M.F. Songster, J. Vagner, F. Albericio, and G. Barnay, J. Am. Chem. Soc. 1998, 120, 5441 - 5452; J. Alsina, K.J. Jensen, F. Albericio, and G. Barany, Chem. Eur. J. 1999, 5 (10), 2787 - 2795) as well as for the synthesis of heterocyclic compounds (T.F. Herpin, K.G. Van 35 Kirk, J. M. Savino, S. T. Yu, and R. F. Labaudiniare, J. Comb. Chem. 2000, 2, 513 - 521, M. del Fresno, J. Alsina, M. Royo, G.
WO 2011/015241 PCT/EP2009/060168 161 Barany, and F. Albericio, Tetrahedron Lett. 1998, 39, 2639 2642; N. S. Gray, S.Kwon, P.G. Schultz, Tetrahedron Lett. 1997, 38 (7), 1161 - 1164). 5 Examples of resins functionalized by such linker structures include DFPE polystyrene (2-(3,5-dimethoxy-4 formylphenoxy)ethyl polystyrene), DEPEM polystyrene (2-(3,5 dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene), FMPB resins (4-(4-formyl-3-methoxyphenoxy)butyryl AM resin), FMPE 10 polystyrene HL (2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL), FMPB NovaGel TM (4-(4-formyl-3-methoxyphenoxy)butyryl NovaGelTM; a PEG PS resin). The macrocyclic primary amine is attached to such solid support 15 by means of reductive amination preferably using NaBH(OAc) 3 in 1,2 dichloroethane in the presence of trimethyl orthoformate. The use of reductive amination to couple amines to resins with the above mentioned linker is well documented; for example 20 NaBH 3 CN in DMF or in methanol, or NaBH (OAc)3 in DMF / acetic acid or in dichloromethane / acetic acid have been used (see K.J. Jensen, J. Alsina, M.F. Songster, J. Vagner, F. Albericio, and G. Barany, J. Am. Chem. Soc. 1998, 120, 5441 - 5452; J. Alsina, K.J. Jensen, F. Albericio, and G. Barnay, Chem. Eur. J. 25 1999, 5 (10), 2787 - 2795; T.F. Herpin, K.G. Van Kirk, J. M. Savino, S. T. Yu, and R. F. Labaudiniere, J. Comb. Chem. 2000, 2, 513 - 521; A. L. Vergnon, R.S. Pottorf, M. R. Player, J. Comb. Chem. 2004, 6, 91 - 98.). These authors also describe a variety of conditions for the acylation of the resulting 30 secondary amine, using carboxylic acid and coupling reagents including PyBOP, PyBroP, HATU as well as carboxylic acid fluorides or carboxylic acid anhydrides. The second functional group is an Alloc or Fmoc protected amino 35 group or a carboxyl group protected as allyl ester. Standard WO 2011/015241 PCT/EP2009/060168 162 conditions are applied to deprotect and derivatize these functional groups. The final products are detached from the solid support by means 5 of acid in organic solvents or in H 2 0. The use of TFA in dichloromethane, TFA in dichloromethane in the presence of a scavenger such as H 2 0 or dimethyl sulfide, or of TFA /H 2 0 and
TFA/H
2 0/dimethylsulfide has been described, references see above. 10 Macrocyclic compounds of general formula I with highly variable amino acid side chain motifs in bridge c can advantageously be prepared in a parallel array synthesis on solid support. This synthesis comprises immobilization of an appropriately 15 protected and functionalized precursor comprising building blocks A, B and subsequent coupling of one to three amino acids c1, c2 and c3, followed by cylization and release of the product thus obtained. 20 The corresponding process comprises: a 6 ) condensation of a suitable hydroxy or mercapto aryl/heteroaryl carboxylic acid ester H-A-OPG7 with an appropriately N-protected amino alcohol HO-B-PG 8 , substituted with an orthogonally protected primary amino group, applying 25 the methods discussed above; b 6 ) removal of the protective group of the primary amine; c 6 ) attachment of the product obtained in step b 6 ) to the solid support in a reductive alkylation step in analogy to the previously described process providing a polymer-supported 30 fragment PG 8 -B-A-0-PG 7 with free secondary side chain amino group; d 6 ) acylation, carbamoylation, oxycarbonylation or sulfonylation of the secondary amine obtained in step c'); e ) cleavage of the "main chain" amine protective group (PG8); 35 f") coupling of a appropriately N-terminal protected amino acid
PG
9 -c3-OH; WO 2011/015241 PCT/EP2009/060168 163 g') removal of the N-terminal protective group (PG 9 ) of the product obtained in step f 6 ); h') next coupling to introduce amino acid PG 9 -cl-OH (for target compounds with bridges comprising two amino acid building 5 blocks), or coupling/deprotection cycle to introduce amino PG 9 c2-OH followed by coupling of amino acid PG 9 -cl-OH (for target compounds with bridges comprising three amino acid building blocks) by effecting steps corresponding to f6) and g 6 ); i 0 ) cleavage of the aryl/heteroaryl ester group (PG 7 ); 10 j 6 ) cleavage of the N-terminal protective group (PG 9 ); k') macrolactamization of the linear cyclization precursor on solid support (for an example of cyclization on solid support see the synthesis of cyclic peptides attached to the solid support with the side chain as described by C. Cabrele, M. 15 Langer, and A.G. Beck-Sickinger, J. Org. Chem. 1999, 64, 4353 4361.); and 16) detachment of the final product. As an alternative, the linear cyclization precursor obtained in 20 step j') can be released from the solid support and cyclized in solution by k 6 ') detachment of the linear cyclization precursor; and 16') macrolactamization in solution. 25 In a parallel array synthesis soluble coupling reagents as described above as well as polymer supported coupling reagents such as N-cyclohexyl-carbodiimide-N'-methylpolystyrene or N alkyl-2-chloro pyridinium triflate resin (S. Crosignani, J. Gonzales, D. Swinnen, Org. Lett. 2004, 6 (24), 4579 - 4582) may 30 be used. Further alternatives include ring closure in other positions, for example between amino acids c1 and c2. 35 WO 2011/015241 PCT/EP2009/060168 164 Thus a precursor with two amino acids coupled to the immobilized precursor would be prepared (polymer supported PG9 c2-c3-B-A-OPG 7 ) by effecting steps corresponding to steps a') to h ) described in the above paragraph. The subsequent steps 5 then comprise i 6 ') cleavage of the aryl/heteroaryl ester group (PG'); j') coupling of an appropriately C-terminal protected amino acid H-cl-OGP 7 ; 10 k 6 ') cleavage of the c-terminal protective group (PG); 16,) cleavage of the N-terminal protective group (PG9) and
M
6 ') macrolactamization either on solid support or in solution after detachment of the linear precursor from the solid support. 15 The macrocycles of formula I of the present invention interact with specific biological targets. In particular, they show agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT2B (5-HT 2 B receptor), and on the prostaglandin F2a receptor (FP receptor). 20 Accordingly, these compounds are useful for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis and constipation type irritable bowl syndrome; for the treatment of CNS related diseases like migraine, schizophrenia, psychosis or depression; for the 25 treatment of ocular hypertension such as associated with glaucoma and for preterm labour. The macrocycles, as such or after further optimization, may be administered per se or may be applied as an appropriate 30 formulation together with carriers, diluents or excipients well-known in the art. When used to treat or prevent the diseases mentioned above the macrocycles can be administered singly, as mixtures of several 35 macrocycles, or in combination with other pharmaceutically WO 2011/015241 PCT/EP2009/060168 165 active agents. The macrocycles can be administered per se or as pharmaceutical compositions. Pharmaceutical compositions comprising macrocycles of the 5 invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically 10 acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active macrocycles into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen. 15 For topical administration the macrocycles of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration 20 by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. 25 For injections, the macrocycles of type I may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or 30 dispersing agents. Alternatively, the macrocycles of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use. For transmucosal administration, penetrants appropriate to the 35 barrier to be permeated are used in the formulation as known in the art.
WO 2011/015241 PCT/EP2009/060168 166 For oral administration, the compounds can be readily formulated per se or by combining the active macrocycle of the invention with pharmaceutically acceptable carriers well known 5 in the art. Such carriers enable the macrocycles of type I to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients 10 include fillers such as sugars, (e.g. lactose, sucrose, mannitol or sorbitol) or such as cellulose preparations (e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose); and/or granulating 15 agents; and/or binding agents such as polyvinylpyrrolidone (PVP). If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard 20 techniques. For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In 25 addition, flavoring agents, preservatives, coloring agents and the like may be added. For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual. 30 For administration by inhalation, the macrocycles of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. hydrofluoroalkanes (HFA) such as HFA 35 134a (1,1,1,2,-tetrafluoroethane); carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose WO 2011/015241 PCT/EP2009/060168 167 unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the macrocycles of the invention and a suitable 5 powder base such as lactose or starch. The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases like cocoa butter or other glycerides. 10 In addition to the formulations described afore, the macrocycles of the invention may also be formulated as depot preparations. Such slow release, long acting formulations may be administered by implantation (e.g. subcutaneously or 15 intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the macrocycles of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts. 20 In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the macrocycles of type I may be 25 delivered using a sustained-release system, such as semi permeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well-known by those skilled in the art. Sustained-release capsules may, depending on their chemical 30 nature, release the compounds over a period of a few days up to several months. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for stabilization may be employed. 35 As the macrocycles of the invention may contain charged residues, they may be included in any of the above-described WO 2011/015241 PCT/EP2009/060168 168 formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than the corresponding free base or acid forms. 5 The macrocycles of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application. 10 For example, the therapeutically effective dose for an systemic administration can be estimated initially from in vitro assays: A dose can be formulated in animal models to achieve a circulating macrocycle concentration range that includes the
IC
0 or EC5 0 as determined in the cell culture (i.e. the 15 concentration of a test compound that shows half maximal inhibitory concentration in case of antagonists or half maximal effective concentration in case agonists). Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be determined from in vivo data, e.g. 20 animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data. Dosage amounts for applications such as gastroparesis or 25 schizophrenia etc. may be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day. 30 In cases of local administration or selective uptake, the effective local concentration of the macrocycles of the invention may not be related to plasma concentration. Those having the ordinary skill in the art will be able to optimize 35 therapeutically effective local dosages without undue experimentation.
WO 2011/015241 PCT/EP2009/060168 169 The amount of macrocycle administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of 5 administration and the judgment of the prescribing physician. Normally, a therapeutically effective dose of the macrocycles described herein will provide therapeutic benefit without causing substantial toxicity. 10 Toxicity of the macrocycles of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) or the LDioo (the dose lethal 15 to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in 20 humans. The dosage of the macrocycles of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized. The exact 25 formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (cf. E. Fingl et al., The Pharmacological Basis of Therapeutics, 59 ed. 1975 (Ed. L. Goodman und A. Gilman), Ch.1, p.1). 30 A further embodiment of the present invention may also include compounds, which are identical to the compounds of formula I, except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass 35 number or mass usually found in nature, e.g. compounds enriched in 2H (D) , 'H, 'C, ' 4 C, 1 2I etc. These isotopic analogs and WO 2011/015241 PCT/EP2009/060168 170 their pharmaceutical salts and formulations are considered useful agents in the therapy and/or diagnostic, for example, but not limited to, where a fine-tuning of in vivo half-life time could let to an optimized dosage regimen. 5 Examples 10 The following Examples illustrate the invention in more detail but are not intended to limit its scope in any way. The following abbreviations are used in these Examples: ADDP: azodicarboxylic dipiperidide 15 All: allyl Alloc: allyloxycarbonyl AllocCl: allyl chloroformate AllocOSu: allyloxycarbonyl-N-hydroxysuccinimide AM-resin: aminomethyl resin 20 aq.: aqueous arom.: aromatic BnBr: benzyl bromide Boc: tert-butoxycarbonyl br.: broad 25 Cbz: benzyloxycarbonyl CbzOSu: N- (benzyloxycarbonyloxy)succinimide Cl-HOBt: 6-chloro-l-hydroxybenzotriazole CMBP: cyanomethylenetributyl-phosphorane m-CPBA: 3-chloroperbenzoic acid 30 d: day(s) or doublet (spectral) DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DEAD: diethyl azodicarboxylate DFPE polystyrene: 2-(3,5-dimethoxy-4-formylphenoxy)ethyl 35 polystyrene DIAD: diisopropyl azodicarboxylate WO 2011/015241 PCT/EP2009/060168 171 DIC: N,N'-diisopropylcarbodiimide DMF: dimethylformamide DMSO: dimethyl sulfoxide DPPA: diphenyl phosphoryl azide 5 DVB: divinylbenzene EDC: 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide equiv.: equivalent Et 3 N: triethylamine EtOAc: ethyl acetate 10 FC: flash chromatography FDPP: pentafluorophenyl diphenylphosphinate Fmoc: 9-fluorenylmethoxycarbonyl h: hour(s) HATU: O-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 15 hexafluorophosphate HBTU: O-(benoztriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCTU: O-(lH-6-chlorobenoztriazol-1-yl)-N,N,N',N' tetramethyluronium hexafluorophosphate 20 HOAt: 1-hydroxy-7-azabenzotriazole HOBt.H20: 1-hydroxybenzotriazole hydrate HMPA: hexamethylphosphoramide i.v.: in vacuo m: multiplet (spectral) 25 MeOH: methanol NMP: 1-methyl-2-pyrrolidinone Pd(PPh 3 )4: Tetrakis (triphenylphosphine)palladium(0) PEG PS resin: polyethyleneglycol coated polystyrene resin PG: protective group 30 PPh 3 : triphenylphosphine prep.: preparative i-Pr 2 NEt: N-etyl-N,N-diisopropylamine PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate 35 PyBroP: Bromotripyrrolidinophosphonium hexafluorophosphate q: quartet (spectral) WO 2011/015241 PCT/EP2009/060168 172 quant.: quantitative sat.: saturated soln: solution t: triplet (spectral) 5 TBAF: tetrabutylammonium fluoride Teoc: 2-(trimethylsilyl)ethoxycarbonyl TeocONp: 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate TFA: trifluoroacetic acid THF: tetrahydrofuran 10 tlc: thin layer chromatography T3PTM: propanphosphonic acid cyclic anhydride p-TsOH: p-toluenesulfonic acid 15 General Methods TLC: Merck (silica gel 60 F254, 0.25 mm). Flash chromatography (FC): Fluka silica gel 60 (0.04-0.063 mm) and Interchim Puriflash IR 60 silica gel (0.04-0.063 mm). 20 I. Analytical HPLC-MS methods: Rt in min (purity at 220 nm in %), m/z [M+H]r 25 Volume of injection: 5 ptL for all methods Method la and lb XBridge C18 2.5 pm, 2.1x50 mm Column: (186003085 - Waters) Mobile Phases A: 0.1% TFA in Water 0.085% TFA in B: Acetonitrile Column oven temp. 450 C Time Flow Gradient (min.) (pl/min) %A %B 0 500 97 3 0.1 500 97 3 3 500 3 97 WO 2011/015241 PCT/EP2009/060168 173 3.6 500 3 97 3.7 500 97 3 4.3 500 97 3 Method 1, cont. UV Wavelenght: 220 nm 254 nm Method la 100-800 Da Method lb Centroid MS scan Range: 300-2000 Da mode Scan Time: 1 sec. Ionization type: Electrospray Method 2 Gemini NX C18 3 pm, 2.1x5O mm Column: (OOB-4453-BO - Phenomenex) Mobile Phases A: 0.1% TFA in Water 0.085% TFA in B: Acetonitrile Column oven temp. 450 C Time Flow Gradient (min.) (pl/min) %A %B 0 800 97 3 0.1 800 97 3 2.2 800 3 97 2.5 800 3 97 2.55 1000 97 3 2.75 1000 97 3 2.8 800 97 3 UV Wavelenght: 220 nm 254 nm Centroid MS scan Range: 100-2000 Da mode Scan Time: 1 sec. Ionization type: Electrospray Method 3 Gemini NX C18 3 pm, 2.1x50 mm Column: (OOB-4453-BO - Phenomenex) 1 mM ammonium Mobile Phases A: bicarbonate pH 10 B: Acetonitrile Column oven temp. 450 C Time Flow Gradient (min.) (pl/min) %A %B 0 800 97 3 0.1 800 97 3 WO 2011/015241 PCT/EP2009/060168 174 2.2 800 3 97 2.5 800 3 97 2.55 1000 97 3 2.75 1000 97 3 2.8 800 97 3 Method 3, cont. UV Wavelenght: 220 nm 254 nm Centroid MS scan Range: 100-2000 Da mode Scan Time: 1 sec. Ionization type: Electrospray Method 4a-4b Gemini NX C18 3 pm, 2.1x50 mm Column: (OOB-4453-BO - Phenomenex) Mobile Phases A: 0.1% TFA in Water 0.085% TFA in B: Acetonitrile Column oven temp. 450 C Time Flow Gradient (min.) (pl/min) %A %B 0 800 97 3 0.1 800 97 3 2.7 800 3 97 3 800 3 97 3.05 1000 97 3 3.25 1000 97 3 3.3 800 97 3 UV Wavelenght: 220 nm 254 nm Method 4a Centroid 100-2000 Da mode Method 4b Profile MS scan Range: 350-2000 Da mode Scan Time: 1 sec. Ionization type: Electrospray 5 Method 5a-5b Gemini NX C18 3 pm, 2.1x50 mm Column: (OOB-4453-BO - Phenomenex) 1 mM ammonium Mobile Phases A: bicarbonate pH 10 B: Acetonitrile Column oven temp. 450 C Time Flow Gradient (min.) (pl/min) %A %B 0 800 97 3 WO 2011/015241 PCT/EP2009/060168 175 0.1 800 97 3 2.7 800 3 97 3 800 3 97 3.05 1000 97 3 3.25 1000 97 3 3.3 800 97 3 Method 5, cont. UV Wavelenght: 220 nm 254 nm Method 5a Centroid 100-2000 Da mode Method 5b Profile MS scan Range: 350 - 2000 Da mode Scan Time: 1 sec. Ionization type: Electrospray Method 6 Acquity UPLC BEH C18 1.7 pm, 2.1x50 mm Column: (cod. 186002350 - Waters) Mobile Phases A: 0.1% TFA in Water 0.085% TFA in B: Acetonitrile Column oven temp. 550 C Time Flow Gradient (min.) (pl/min) %A %B 0 1250 97 3 0.05 1250 97 3 1.65 1250 3 97 1.95 1250 3 97 2.00 1250 97 3 2.30 1250 97 3 UV Wavelenght: 220 nm 254 nm Centroid MS scan Range: 100-1650 Da mode 0.5 Scan Time: sec. Ionization type: Electrospray 5 Method 7 Acquity UPLC BEH C18 1.7 pm, 2.1x50 mm Column: (cod. 186002350 - Waters) Mobile Phases A: 0.1% TFA in Water 0.085% TFA in B: Acetonitrile Column oven temp. 550 C Time Flow Gradient (min.) (pl/min) %A %B WO 2011/015241 PCT/EP2009/060168 176 0 1250 97 3 0.05 1250 97 3 1.65 1250 3 97 1.95 1250 3 97 2.00 1250 97 3 2.30 1250 97 3 Method 7, cont. UV Wavelenght: 220 nm 254 nm Profile MS scan Range: 100-1650 Da mode 0.5 Scan Time: sec. Ionization type: Electrospray Method 8 Acquity UPLC BEH C18 1.7 pm, 2.1x50 mm Column: (cod. 186002350 - Waters) 1 mM ammonium Mobile Phases A: bicarbonate pH 10 B: Acetonitrile Column oven temp. 550 C Volume of injection: 5 gl Time Flow Gradient (min.) (pl/min) %A %B 0 1250 97 3 0.05 1250 97 3 1.65 1250 3 97 1.95 1250 3 97 2.00 1250 97 3 2.30 1250 97 3 UV Wavelenght: 220 nm 254 nm Profile MS scan Range: 100-1650 Da mode 0.5 Scan Time: sec. Ionization type: Electrospray 5 10 Method 9a-9c Column: Acquity UPLC BEH C18 1.7 pm, 2.lxlOO mm WO 2011/015241 PCT/EP2009/060168 177 (cod. 186002352 - Waters) 0.1% TFA in Water / Acetonitrile Mobile Phases A: 95/5 v/v 0.085% TFA in B: Acetonitrile Column oven temp. 550 C Method 9, cont. Time Flow Gradient (min.) (pl/min) %A %B 0 700 99 1 0.2 700 99 1 2.5 700 3 97 2.85 700 3 97 2.86 700 99 1 3.20 700 99 1 UV Wavelenght: 220 nm MS scan Range: Method 9a: 100-800 Da; Method 9b: 100 - 1200 Da; Method 9c: 200 - 1400 Da Profile mode Scan Time: 1 sec. Ionization type: Electrospray Analytical HPLC (x% CH 3 CN) : Rt in min (purity at 220 nm in %) 5 Column: Develosil RPAq 5 pM, 4.6 x 50 mm; Flow rate: 1.5 ml/min 0. 0-0. 5 min (x% CH 3 CN, 100-x% H20 containing 0. 1% TFA); 0.5-5.0 min (x% CH 3 CN, 100-x% HO containing 0.1% TFA to 100%
CH
3 CN) 10 5.0-6.2 min (100% CH 3 CN) II. Preparative HPLC methods: 15 1. Reverse Phase - Acidic conditions Column: XBridge C18 5 pm, 30 x 150 mm (Waters) Mobile phases: 20 A: 0.1% TFA in Water/Acetonitrile 95/5 v/v WO 2011/015241 PCT/EP2009/060168 178 B: 0.1% TFA in Water/Acetonitrile 5/95 v/v 2. Reverse Phase - Basic conditions 5 Column: XBridge C18 5 pm, 30 x 150 mm (Waters) Mobile phases: A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 95/5 v/v B: Acetonitrile 10 3. Normal Phase Column: VP 100/21 NUCLEOSIL 50-10, 21 x 100 mm (Macherey-Nagel) Mobile phases: A: Hexane 15 B: Ethylacetate C: Methanol 20 NMR Spectroscopy: Bruker Avance 300, 'H-NMR (300 MHz) in the indicated solvent at ambient temperature. Chemical shifts 6 in ppm, coupling constants J in Hz. 25 The term "isomers" comprises in the present invention species of identical chemical formula, constitution and thus molecular mass, such as but not limited to amide cis/trans isomers, rotamers, conformers, diastereomers. 30 Examples 35 Starting materials Building Blocks of Type A (Scheme 1): 2-Acetoxy-5-fluoro benzoic acid (2) was prepared according to the method of C. M. Suter and A. W. Weston, J. Am. Chem. Soc. 40 1939, 63, 2317-2318.
WO 2011/015241 PCT/EP2009/060168 179 3-Acetoxybenzoic acid (3) is commercially available. 4-Acetoxybenzoic acid (4) is commercially available. 5 5-Hydroxy nicotinic acid (5) is commercially available. 8-Acetoxyquinoline-2-carboxylic acid (8) was prepared according to the method of R.W. Hay, C.R. Clark, J. Chem. Soc. Dalton 1977, 1993-1998. 10 (S)-2-tert-Butoxycarbonylamino-8-hydroxy-1,2,3,4-tetrahydro naphthalene-2-carboxylic acid (10) was prepared according to the method of M. M. Altorfer, Dissertation Universitdt Zurich, 1996. 15 3-Mercaptobenzoic acid (11) is commercially available Building Blocks of Type B (Scheme 2): 20 tert-Butyl (3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate (13) as well as the corresponding HCl salt (13*HCl) are commercially available. 25 tert-Butyl (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate (17) as well as the corresponding HCl salt (17'HCl) are commercially available. (S)-tert-Butyl 3-(hydroxymethyl)piperazine-l-carboxylate 30 hydrochloride (21-HCl) is commercially available. (R)-tert-Butyl 3-(hydroxymethyl)piperazine-l-carboxylate hydrochloride (83'HCl) (Scheme 5) is commercially available. 35 (2S,4S)-Allyl 2-(hydroxymethyl)-4-((2 (trimethylsilyl)ethoxy)carbonylamino)pyrrolidine-l-carboxylate WO 2011/015241 PCT/EP2009/060168 180 (16) was prepared in three steps (1. Alloc protection of the secondary amino group with allyloxycarbonyl-N hydroxysuccinimide (AllocOSu) in CH 2 Cl2, 2. cleavage of the Boo group with dioxane-HCl; 5 3. Teoc protection of the primary amino group with 2 (trimethylsilyl)ethyl 4-nitrophenyl carbonate (Teoc-ONp) in
CH
2 Cl2 in the presence of EtsN) from amino alcohol 13, applying standard conditions; as leading references cf. T.W. Greene, P.G.M. Wuts, Protective Groups in Organic 10 Synthesis, 3rd edition, John Wiley & Sons, 1999; P.J. Kocienski, Protecting Groups, 3rd edition, Georg Thieme Verlag, 2005. Data of 16: C15H 2 8NOSi (344.5): Flow injection MS (APCI): 689 ([2M+H]+) , 345 ( [M+H]K) . H-NMR (DMSO-d 6 ): 7.28 (d, J = 6.1, 1 15 H), 5.90 (m, 1 H), 5.25 (qd, J = 1.7, 17.2, 1 H), 5.16 (qd, J = 1.5, 10.5, 1 H), 4.90 (br. t, 1 H), 4.54-4.42 (m, 2 H), 4.04 3.97 (m, 2 H), 3.90 (q, J = 6.8, 1 H), 3.80-3.66 (br. m and dd, 2 H), 3.57-3.43 (br. m, 2 H), 2.96 (br. m, 1 H), 2.19 (br. m, 1 H), 1.78 (br. m, 1 H), 0.89 (t, J ca 8.3, 2 H), 0.00 (s, 9 H) 20 (2S,4R)-Allyl 2-(hydroxymethyl)-4-((2 (trimethylsilyl)ethoxy)carbonylamino)pyrrolidine-l-carboxylate (20) was prepared from amino alcohol hydrochloride 17'HCl, 25 applying the same transformations as described for the synthesis of diastereomer 16 with the exception of the Alloc protection step which was performed using allyl chloroformate in CH 2 C1 2 in the presence of aqueous NaHCO 3 solution. Data of 20: C-H 2 bN>0 5 Si (344.5) : LC-MS (method 9a) : Rt = 1.98, 30 345 ([M+H]K); 317; 259. H-NMR (DMSO-dG) : 7.26 (d, J = 6.6, 1 H), 5.89 (m, 1 H), 5.25 (br. d, J = 17.0, 1 H), 5.15 (br. d, J = 10.2, 1 H), 4.75 (m, 1 H), 4.48 (m, 2 H), 4.16-3.98 (m, 3 H), 3.82 (br. m, 1 H), 3.48-3.30 (m, 3 H), 3.21 (m, 1 H), 2.01 (m, 1 H), 1.80 (m, 1 H), 0.89 (t, J = 8.3, 2 H), 0.00 (s, 9 H). 35 WO 2011/015241 PCT/EP2009/060168 181 (S)-l-Allyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4 dicarboxylate (22) was prepared from amino alcohol hydrochloride 21'HCl, applying allyl chloroformate in CH 2 Cl 2 in the presence of aqueous NaHCO 3 solution; as leading references 5 cf. T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1999; P.J. Kocienski, Protecting Groups, 3rd edition, Georg Thieme Verlag, 2005. Data of 22: C 4
H
24
N
2 0 5 (300.4): LC-MS (method 9a): Rr = 1.70, 201 10 ([M+H]) . 'H-NMR (DMSO-d 6 ): 5.90 (m, 1 H), 5.29 (qd, J = 1.7, 17.3, 1 H), 5.18 (qd, J = 1.5, 10.5, 1 H), 4.81 (t, J = 4.9, 1 H), 4.53 (d-like m, J ca. 5.1, 2 H), 4.04-3.75 (br. m, 4 H), 3.39 (m, 2 H), 2.95-2.70 (br. m, 3 H), 1.40 (s, 9 H). 15 Building Blocks of Type C (Scheme 3): (S)-5-Allyl 1-benzyl 2-(methylamino)pentanedioate hydrochloride 20 (27'HCl) A mixture of Boc-L-Glu(OAll)OH (23; 33 g, 115 mmol) and NaHCO (27 g, 322 mmol) in DMF (500 mL) was stirred for 1 h at room temperature followed by the slow addition of benzyl bromide (35 mL, 299 mmol) in DMF (15 mL). Stirring was continued for 16 h 25 followed by aqueous workup (diethyl ether, sat. aq. NaHCO 3 soln, sat aq. NaCl soln) and purification by FC (CH2Cl 2 /MeOH 100:0 to 98:2) to give the corresponding benzyl ester (34.4 g, 79%), which was dissolved in dioxane (40 mL) and treated with 4 M HCl-dioxane (400 mL) for 1 h. The volatiles were evaporated. 30 The residue was crystallized from diethyl ether to afford 24'HCl (23.8 g, 83%). 4-Nitrobenzenesulfonyl chloride (39 g, 178 mmol) was added at O*C to a solution of 24'HCl (46.5 g, 148 mmol) and pyridine (42 mL, 519 mmol) in CH 2 C12 (700 mL) . The mixture was stirred for 35 15 h followed by aqueous workup (CH2Cl2, 1 M aq. HCl soln) and WO 2011/015241 PCT/EP2009/060168 182 purification of the crude by FC (hexane/EtOAc 80:20 to 75:25) to yield 25 (55.54 g, 81%). A solution of 25 (41.3 g, 89 mmol) in dry DMF (200 mL) was cooled to O0C. Methyliodide (5.8 mL, 94 mmol) in DMF (100 mL) 5 was slowly added, followed by a solution of DBU (14 mL, 94 mmol) in DMF (100 mL). The mixture was stirred for 4 h at room temperature followed by aqueous workup (EtOAc, 1 M aq. HCl soln., H 2 0, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln) to afford 26 (42.8 g, 99%). 10 A solution of 26 (17.4 g, 37 mmol) in dry, degassed CH 3 CN (270 mL) was treated with thiophenol (6.7 mL, 66 mmol) and Cs2CO 3 (39 g, 121 mmol) at room temperature for 16 h. The mixture was filtered and the residue was washed with diethyl ether. The filtrate was carefully concentrated (bath temperature 200C) and 15 immediately purified by FC (hexane/EtOAc 80:20 to 50:50). The combined product fractions were carefully concentrated, immediately treated with 4 M HCl-dioxane (20 mL) for 5 min and concentrated to give 27HCl (8.62 g, 72%). Data of 27'HCl: ClcH 2 1
NO
4 HCl (291.3, free base). LC-MS (method 20 9b): R, = 1.44, 292 ([M+H]) . -H-NMR (DMSO-d) : 9.57 (br. s, NH2), 7.45-7.34 (m, 5 arom. H), 5.88 (M, 1 H), 5.32-5.19 (m, 4 H), 4.53 (td, J = 1.3, 5.4, 1 H), 4.13 (br. t, J ca. 6.0, 1 H), 2.69-2.40 (m, 2 H), 2.56 (s, 3 H), 2.30-2.05 (m, 2 H). 25 (R)-5-Allyl 1-benzyl 2-(methylamino)pentanedioate hydrochlorided (29'HCl) was prepared from Boc-D-Glu(OAll)OH (28) applying the methods described above for the synthesis of the enantiomer (27'HCl). 30 Data of 29-HCl: C2 6 H2 1
NO
4 HCl (291.3, free base) . LC-MS (method 9b): Rt = 1.44, 292 ([M+H]') . -H-NMR (DMSO-d 6 ): 9.92 (br. s, NH+), 9.54 (br. s, NH+), 7.45-7.34 (m, 5 arom. H), 5.88 (M, 1 H), 5.32-5.19 (m, 4 H), 4.53 (td, J = 1.3, 5.4, 1 H), 4.13 (br. t, J ca. 6.0, 1 H), 2.69-2.40 (m, 2 H), 2.56 (s, 3 H), 2.30 35 2.05 (m, 2 H).
WO 2011/015241 PCT/EP2009/060168 183 (S)-Allyl 2-(benzyloxycarbonylamino)-3-(methylamino)propanoate hydrochloride (32'HCl) Cbz-L-SerOH (30) was converted into amino acid 31 by $-lactone 5 formation and opening with HNCH 3 Si(CH 3 )3 (see J. Kim, S. G. Bott, D.M. Hoffman Inorg. Chem. 1998, 37, 3835-3841), following the procedures of J.K. Kretsinger and J.P. Schneider, J. Am. Chem. Soc. 2003, 125, 7907-7913 and E.S. Ratemi and J.C. Vederas, Tetrahedron Lett. 1994, 35, 7605-7608. 10 A solution of 31'HCl (2.2 g, 7.6 mmol) in allyl alcohol (55 mL) was treated with thionyl chloride (1.7 mL, 23 mmol) for 15 min at room temperature and for 1.5 h at 70'C. The volatiles were evaporated. The crude product was dissolved in CH 2 Cl2 and washed with aq. NaHCO 3 solution. The aqueous layers were 15 extracted with CH 2 C1 2 and with EtOAc. The combined organic phase was dried (Na 9 SO4), filtered, and concentrated. The resulting oil (2.18 g) was dissolved in CH 2 C1 2 (80 mL), treated with 4 M HCl-dioxane (20 mL), stirred for 5 min and concentrated to afford 32-HCl (2.5 g, quantitative). 20 Data of 32'HCl: CH 20 N204'HCl (292.3, free base) . LC-MS (method 9a): RL = 1.26, 293 ([M+H]K). H-NMR (DMSO-dc): 9.20 (br. s, NH'), 9.03 (br. s, NH), 8.02 (d, J = 8.2, NH), 7.38-7.30 (m, 5 arom. H), 5.89 (m, 1 H), 5.33 (d, J = 17.3, 1 H), 5.23 (d, J = 10.5, 1 H), 5.08 (s, 2 H), 4.63 (d, J = 5.3, 2 25 H), 4.56 (m, 1 H), 3.35 (br. m, 1 H), 3.25 (br. m, 1 H), 2.56 (br. s, 3 H). As an alternative, 32'HCl was prepared from Cbz-L-DapOH applying the method described below for the synthesis of the 30 enantiomer 36'HCl. (R)-Allyl 2-(benzyloxycarbonylamino)-3-(methylamino)propanoate hydrochloride (36'HCl) WO 2011/015241 PCT/EP2009/060168 184 Cbz-D-DapOH was converted into the allylester-pTsOH salt 33-pTsOH according to the procedure of T.M. Kamenecka and S.J. Danishefsky, Chem. Eur. J. 2001, 7, 41-63, describing the synthesis of D-threonine allyl ester. 5 The amino ester 33'pTsOH was converted into the free base by extraction (CH 2 C1 2 , sat. aq. NaHCO 3 soln) and treated with 4 nitrobenzenesulfonyl chloride (1.05 equiv.) in CH 2 Cl2 in the presence of pyridine (3.0 equiv.) to give the p-nitrophenyl sulfonamide 34. 10 At 00C, a solution of methyl iodide (2.3 mL, 37 mmol) in DMF (80 mL) was added to a solution of 34 (16.4 g, 35 mmol) in DMF (80 mL). A solution of DBU (5.6 mL, 37 mmol) in DMF (80 mL) was slowly added over 2 h. The mixture was stirred at room temperature for 1.5 h, followed by an aqueous workup (EtOAC, 1 15 M HCl soln, H 2 0, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln) to afford 35 (17.07 g, quant.). At 00C, thiophenol (3.02 mL, 29.6 mmol) was added (dropwise, rapidly) to a mixture of 35 (7,85 g, 16.5 mmol) and K2CO 3 (7.95 g, 57.5 mmol) in DMF (78 mL). The mixture was stirred for 2.5 h 20 at 0-10'C. The mixture was diluted with EtOAc and washed with H20 and sat. aq. NaCl soln. The organic layer was extracted with ice-cold 1 M aqueous HCl soln. The aqueous phase (base extract) was poured onto aqueous NaCO 3 soln to reach pH ca 7; 2 M aq. NaOH soln. was added to reach pH ca 10, followed by 25 extraction with EtOAc. The organic phase was dried (Na 2
SO
4 ) and concentrated. The remaining oil (2.72 g) was dissolved in
CH
2 Cl2 (30 mL) and treated with 4 M HCl-dioxane (10 mL) to afford after evaporation of the volatiles 36-HCl (3.34 g, 62%) Data of 36'HCl: CjH N,0 4 'HCl (292.3, free base) . LC-MS (method 30 7): Rt = 0.88, 293 ([M+H]) . H-NMR (DMSO-ds): 9.06 (hr. s, NH'), 8.94 (br. s, NH'), 8.00 (d, J = 8.3, NH), 7.38-7.30 (m, 5 arom. H), 5.88 (m, 1 H), 5.33 (d, J = 17.3, 1 H), 5.23 (d, J = 10.5, 1 H), 5.08 (s, 2 H), 4.63 (d, J = 5.3, 2 H), 4.56 (m, 1 H), 3.35 (hr. m, 1 H), 3.20 (br. m, 1 H), 2.57 (hr. s, 3 H). 35 WO 2011/015241 PCT/EP2009/060168 185 (S)-Allyl 2-(benzyloxycarbonylamino)-4-(methylamino)butanoate hydrochloride (40'HCl) Cbz-L-DabOH (37) was converted into the allylester-pTsOH salt 38'pTsOH according to the procedure of T.M. Kamenecka and S.J. 5 Danishefsky, Chem. Eur. J. 2001, 7, 41-63, describing the synthesis of D-threonine allyl ester. A mixture of 38'pTsOH (45 g, 97 mmol) in CH 2 Cl 2 (600 mL) was cooled to 0 0 C. MeOH (60 mL) was added, followed by ethyl trifluoroacetate (23 mL, 194 mmol) . Et 3 N (53 mL, 387 mmol) was 10 added dropwise. The mixture was stirred at 0 C for 15 min, then at room temperature for 4 h. The volatiles were evaporated. The residue was dissolved in EtOAc, washed (1 M aq. HCl soln, sat. aq. Na2CO3 soln), dried (Na 2
SO
4 ), filtered and concentrated to afford the corresponding trifluoroacetamide (32 g, 84%). N 15 Methylation of the acetamide (21.78 g, 56 mmol; applying CH3I and K 2
CO
3 in DMF) following the procedure described by Chu-Biao Xue et al. J. Med. Chem. 2001, 44, 2636-2660 - with the exception that the transformation was performed at room temperature for 4 h - afforded 39 (25 g, ca 90%). 20 Treatment of 39 (8.0 g, ca 18 mmol) in THF (80 mL) with Pd(PPhs) 4 (0.2 g) and morpholine (8.5 mL, 98 mmol) at room temperature for 3 h afforded after aqueous workup (EtOAc, 1 M aq HCl soln.) the corresponding trifluoroacetamido acid (7.3 g) which was treated with NH 3 (25% in H 2 O; 50 mL) for 2 h and 25 concentrated to give the corresponding aminoacid (8 g). This material was dissolved in allyl alcohol (150 mL) and treated at 0 0 C with thionyl chloride (6.6 mL, 91 mmol). The mixture was stirred at 0 0 C for 15 min and at room temperature for 3 h and concentrated to give 40-HCl (7.6 g, used in the next step 30 without further purification) Data of 40'HCl: C6H N04'HCl (306.3, free base) . Flow injection MS (ESI, positive modus): 307 ([M+H]). 'H-NMR (DMSO-d 6 ): 8.97 (br. s, NHIJ), 7.92 (d, J = 7.8, NH), 7.40-7.25 (m, 5 arom. H), 5.88 (m, 1 H), 5.32 (d, J = 17.2, 1 H), 5.22 (d, J = 10.5, 1 35 H), 5.05 (s, 2 H), 4.60 (d, J = 5.2, 2 H), 4.22 (m, 1 H), 2.94 WO 2011/015241 PCT/EP2009/060168 186 (m, 2 H), 2.50 (s, 3 H, superimposed by DMSO-d signal), 2.10 (m, 1 H), 2.00 (m, 1 H). 5 (S)-Allyl 2-(benzyloxycarbonylamino)-5-(methylamino)pentanoate hydrochloride (44'HCl) Cbz-L-OrnOH (41) was converted into the allylester-pTsOH salt 10 42-pTsOH according to the procedure of T.M. Kamenecka and S.J. Danishefsky, Chem. Eur. J. 2001, 7, 41-63, describing the synthesis of D-threonine allyl ester. The ester 42'pTsOH (5.5 g, 11 mmol) was converted into 43 (3.97 g, 83%) applying the conditions described for the synthesis of 15 39, with the exception that the N-methylation was continued at room temperature for 8 h. The allyl ester group was then cleaved applying the conditions described for the treatment of 39. The saponification of the resulting trifluoroacetamido acid was performed according to 20 the procedure of Chu-Biao Xue et al. J. Med. Chem. 2001, 44, 2636-2660, with the exception that 2 equiv. of LiOH were used. The resulting amino acid (3.80 g, containing LiCl ca. 9 mmol) was treated at room temperature with allyl alcohol (100 mL) and thionyl chloride (3.0 mL, 41 mmol). The mixture was heated for 25 2 h at 70'C. Stirring was continued at room temperature for 17 h. The volatiles were evaporated. The resulting solid was washed with CH>Cl. to afford 44'HCl (3.62 g, ca 75% w/w; yield 83%, used without further purification). Data of 44'HCl: CjH 4 N04'HCl (320.4, free base) . LC-MS (method 30 9b): Rt = 1.48, 321 ([M+H] ) . H-NMR (DMSO-d 6 ): 9.26 (br. s, NH), 7.86 (d, J = 7.7, NH), 7.39-7.13 (m, 5 arom. H), 5.89 (m, 1 H), 5.31 (br. d, J = 17.3, 1 H), 5.20 (br. d, J = 10.4, 1 H), 5.04 (s, 2 H), 4.58 (d, J = 5.2, 2 H), 4.05 (br. m, 1 H), 2.81 (br. m, 2 H), 2.44 (s, 3 H), 1.80-1.60 (br. m, 4 H), 35 WO 2011/015241 PCT/EP2009/060168 187 Sarcosine allyl ester (46) was prepared as p-TsOH salt applying the procedure of T.M. Kamenecka and S.J. Danishefsky, Chem. Eur. J. 2001, 7, 41-63, describing the synthesis of D-threonine allyl ester. 5 2-((Allyloxycarbonyl) (methyl)amino)acetic acid (47) was prepared according to the method of M. Mori, A. Somada, S. Oida, Chem. Pharm. Bull. 2000, 48, 716-728. 10 3-((Allyloxycarbonyl) (methyl)amino)propanoic acid (49) was prepared applying the method of M. Mori, A. Somada, S. Oida, Chem. Pharm. Bull. 2000, 48, 716-728, describing the synthesis 15 of N-allyloxycarbonylsarcosine. (S)-2-(Benzyloxycarbonylamino)pent-4-enoic acid (51) was prepared from (S)-allylglycine by N-protection (CBzOSu, 20 dioxane, aqueous Na 2 CO3) in analogy to the procedure of D.R. Ijzendoorn, P.N.M. Botman, R.H.Blaauw, Org. Lett 2006, 8, 239 242. Acid 51 was also described by Z-Y Sun, C-H. Kwon, J. N.D. Wurpel, J. Med. Chen. 1994, 37, 2841-2845. 25 General Procedures 30 Synthesis of the A-cl Fragment Procedure A 35 A.1: Acid chloride formation WO 2011/015241 PCT/EP2009/060168 188 Oxalyl chloride (3.5-5.0 equiv.) was added to a mixture of the acetoxyaryl carboxylic acid (Ac-A-OH) and dry diethyl ether or CH2Cl2. The resulting mixture was stirred at room temperature for 15 min followed by the addition of a few drops (ca 50-100 5 pL) of dry DMF. Stirring was continued for 16 h. The mixture was filtered. The filtrate was concentrated and the residue dried i.v. to afford the crude acetoxyaryl carboxylic acid chloride (Ac-A-Cl), which was immediately used in the next step. 10 A.2: Amide coupling A mixture of the amino ester salt (H-cl-OAll'HCl) , the crude acetoxyaryl carboxylic acid chloride (Ac-A-Cl, 1.1-1.5 equiv.) and dry CH 2 Cl 2 or THF was cooled to 0 0 C. An auxiliary base 15 (sym-collidine or i-Pr 2 NEt; 3.0 equiv.) was added dropwise. The mixture was stirred at room temperature for 16 h. The mixture was distributed between EtOAc and 1 M aq. HCl solution. The organic phase was washed (1 M aq. HCl soln., then sat. aq. NaHCO 3 soln. or sat aq. NaCl soln.), dried (\aS0 4 ), filtered 20 and concentrated. FC (hexane/EtOAc gradients) gave the acetoxyaryl amide (Ac-A-cl-OAll). A.3: Deacetylation A solution of acetoxyarylamide (Ac-A-cl-OAll) in dry THF was 25 treated at 0 0 C with 3-dimethylaminopropylamine (3.0-4.5 equiv.). The solution was stirred at room temperature for 1-5 h. The mixture was distributed between EtOAc and icecold 0.1 M or 1 M aq. HCl solution. The organic phase was washed (0.1 or 1 M aq. HCl soln., sat. aq. NaCl soln.), dried (Na2SO 4 ), filtered 30 and concentrated to afford the hydroxyaryl amide (H-A-cl-OAll). Synthesis of the linear cyclization precursor H-B-A-cl-OH 35 Procedure B WO 2011/015241 PCT/EP2009/060168 189 B.1.1: Mitsunobu aryl ether synthesis using PPh 3 /DEAD A mixture of the hydroxyaryl amide (H-A-cl-OAll) and PPh 3 (1.5 equiv.) was dried i.v. for 15 min. Under argon a solution of 5 alcohol (HO-B-Alloc, 1.2 equiv.) in dry benzene was added and the resulting solution was cooled to 0 0 C. A solution DEAD (40% in toluene, 1.2 equiv.) in benzene was slowly added (by syringe pump). The mixture was stirred at room temperature for 18 h and concentrated. FC (hexane/EtOAc gradients) gave the protected 10 amino acid (Alloc-B-A-cl-OAll, sometimes contaminated with byproducts such as e.g. triphenylphosphine oxide, however acceptable for the use in the next step without further purification). 15 B.1.2: Mitsunobu aryl ether synthesis using CMBP A solution of the hydroxyaryl amide (HO-A-cl-OAll), the alcohol (HO-B-Alloc, 1.2-1.3 equiv) and CMBP (2 equiv) was heated in dry toluene at reflux for 3-4 h. The solution was concentrated. FC (hexane/EtOAc gradients) afforded the protected amino acid 20 (Alloc-B-A-cl-OAll). B.2: Cleavage of the allyl/alloc protective groups Pd(PPh 3
)
4 (0.05-0.1 equiv.) was added to a mixture of the 25 protected amino acid (Alloc-B-A-cl-OAll) and 1,3 dimethylbarbituric acid (2.5 equiv.) in degassed EtOAc/CH 2 Cl2 (ca. 1:1). The resulting solution was stirred at room temperature for 1-3 h and concentrated. FC (EtOAC, CH2Cl,/EtOH, or CH2Cl2/MeOH gradients) afforded the free amino acid (H-B-A 30 cl-OH) Synthesis of the linear cyclization precursor H-B-A-cl-c2-OH 35 Procedure C WO 2011/015241 PCT/EP2009/060168 190 C.l: Alloc carbamate formation At 00C, allylchloroformate (1.1 equiv.) was slowly added to a mixture of aminoacid (H-B-A-cl-OH) and Na2CO 3 (1.5-3 equiv.) in 5 dioxane/H20 1:1. The mixture was stirred at room temperature for 15 h. The mixture was diluted with EtOAc and treated with 1 M aq. HCl solution until pH ca 2 was reached. The organic phase was separated, washed (sat. aq. NaCl soln.), dried (Na 2 SO4), filtered, concentrated and dried i.v. to afford the alloc 10 protected amino acid (Alloc-B-A-cl-OH). C.2: Amid coupling i-Pr 9 NEt (5.0 equiv.) was slowly added to a mixture of the alloc protected amino acid (Alloc-B-A-cl-OH), the aminoacid 15 ester salt (H-c2-OAll.p-TsOH, 1.2 equiv.), HOAt (1.5 equiv.) and HATU (1.5 equiv.) in DMF. The mixture was stirred at room temperature for 20 h followed by distribution between EtOAc and ice-cold 0.5 M aq, HCl solution. The organic phase was washed (0.5 M aq. HCl soln., H 0 , sat. aq. NaHCO 3 soln., sat. aq. NaCl 20 soln.), dried (Na 2 SO4), filtered and concentrated. FC (hexane/EtOAc gradients) afforded the protected amino acid (Alloc-B-A-cl-c2-OAll) 25 C.3: Cleavage of the allyl/alloc protective groups Pd(PPh3) 4 (0.1 equiv.) was added to a mixture of the protected amino acid (Alloc-B-A-cl-c2-OAll) and 1,3-dimethylbarbituric acid (2.5 equiv.) in degassed EtOAc/CH2Cl> 1:1. The resulting 30 solution was stirred at room temperature for 1-2 h and concentrated. FC (EtOAC, CH2Cl 2 /EtOH, or CHeClo/MeOH gradients) afforded the free amino acid (H-B-A-cl-c2-OH). 35 Synthesis of the c2-B Fragment WO 2011/015241 PCT/EP2009/060168 191 Procedure D Synthesis in two steps, via amidoester and subsequent saponification i-Pr 2 NEt (5.0 equiv.) was slowly added to a mixture of the N 5 protected amino acid (Alloc-c2-OH, 2.2 equiv.), the aminoalcohol hydrochloride (HO-B-H-HCl), Cl-HOBt (0.25 equiv.) and HCTU (2.5 equiv.) in DMF. The resulting solution was stirred at room temperature for 17 h, followed by distribution between EtOAc and sat. aq. Na 2
CO
3 solution. The organic phase 10 was washed (1 M aq. HCl soln, sat. aq. NaCl soln), dried (HaSO4), filtered and concentrated. FC (hexane/EtOAc or
CH
2 Cl 2 /MeOH gradients) afforded the corresponding amidoester, which was dissolved in THF/H20 4:1 and treated with lithium hydroxide monohydrate (3.0 equiv.) for 2 h at room temperature. 15 The mixture was concentrated to about 50% of the original volume, diluted with EtOAc and extracted with 1 M aq. NaOH solution. The organic phase was washed (H20, sat. aq. NaCl soln), dried (HatSO4), filtered and concentrated to afford the amidoalcohol (HO-B-c2-Alloc). 20 25 Synthesis of the linear cyclization precursor H-c2-B-A-cl-OH Procedure E E.1.1: Mitsunobu aryl ether synthesis using PPh/DEAD 30 A mixture of the hydroxyaryl amide (HO-A-cl-OAll) and PPh 3 (1.5-4.5 equiv.) was dissolved in benzene. The solution was concentrated and the residue was dried i.v. for 15-30 min. Under argon, a solution of the alcohol (HO-B-c2-Alloc, 1.2-2.3 equiv.) in dry and degassed benzene was added and the resulting 35 mixture was cooled to 0 C. A solution of DEAD (40% in toluene, 1.2-4.5 equiv.) was slowly added. The mixture was stirred at WO 2011/015241 PCT/EP2009/060168 192 room temperature for 18 h. In case of incomplete consumption of the hydroxyaryl amide, additional triphenylphosphine (1.0-1.3 equiv.) and DEAD (40% in toluene, 1.0 equiv.) and alcohol (1.0 equiv.) - if consumed according to tlc - were added and 5 stirring was continued for 18 h. The mixture was concentrated. FC (hexane/EtOAc, CH2Cl 2 /EtOH, or CH 2 Cl2/MeOH gradients) afforded Alloc-c2-B-A-cl-OAll (possibly contaminated with byproducts such as e.g. triphenylphosphine oxide, however acceptable for the use in the next step without further 10 purification). E.1.2: Mitsunobu aryl ether synthesis using CMBP CMBP (2-3 equiv.) was added to a mixture of the hydroxyaryl amide (H-A-cl-OAll) and the alcohol (HO-B-c2-Alloc, 1.2-2.2 15 equiv.) in dry toluene. The mixture was heated at reflux for 16 h and concentrated. FC (hexane/EtOAc gradients) afforded the protected amino acid (Alloc-c2-B-A-cl-OA11). E.2: Cleavage of the allyl/alloc protective groups 20 Pd(PPh 3
)
4 (0.05-0.1 equiv.) was added to a mixture of the protected amino acid (Alloc-c2-B-A-cl-OAll) and 1,3 dimethylbarbituric acid (2.4 equiv.) in degassed EtOAc/CH 2 Cl 2 1:1. The resulting solution was stirred at room temperature for 1-3 h and concentrated. FC(EtOAC, CH 2 Cl2/EtOH, or CHICl 2 /MeOH 25 gradients) afforded the free amino acid (H-c2-B-A-cl-OH). Synthesis of the macrocycles cyclo-(B-A-cl), and cyclo-(c2-B-A c1) 30 Procedure F The macrolactamization was typically performed at final concentrations ranging from 0.01 M to 0.001 M 35 F.1.1: T3P mediated lactam formation WO 2011/015241 PCT/EP2009/060168 193 A solution of the precursor (H-B-A-cl-OH or H-c2-B-A-cl-OH or H-B-A-cl-c2-OH, respectively) in dry CH 2 Cl12 was added within 2 h by syringe pump to a solution of T3P (50% in EtOAc, 2 equiv.) and i-PrzNEt (4 equiv.) in dry CH 2 C1 2 . The solution was stirred 5 at room temperature for 20 h, extracted with sat. aq. Na1CO 3 solution and with H 2 0, dried (Na2SO 4 ), filtered and then concentrated. FC (hexane/EtOAc/MeOH or CH2Cl 2 /MeOH gradients) afforded the macrocyclic compound (cyclo-(B-A-cl) or cyclo-(c2 B-A-cl), respectively). 10 F.1.2: FDPP mediated lactam formation A solution of the precursor (H-B-A-cl-OH or H-c2-B-A-cl-OH or H-B-A-cl-c2-OH, respectively) in dry DMF was added within 2 h to a solution of FDPP (2.0 equiv.) in dry DMF. The solution was 15 stirred at room temperature for 20 h. The volatiles were evaporated and the residue taken up in EtOAc and washed (sat. aq. NaHCO 3 soln, H 9 0, sat. aq. NaCl soln) . The organic phase was dried (Na 0
SO
4 ), filtered and concentrated. FC (hexane/EtOAc/MeOH or CHQCl2/MeOH gradients gradients) afforded 20 the macrocyclic compound (cyclo-(B-A-cl) or cyclo-(c2-B-A-cl), respectively). 25 Attachment of substituents to the macrocyclic core structures: Synthesis of the final products Procedure H 30 A solution of a macrocyclic benzylester in MeOH or MeOH/THF (ca 100 mL per g of starting material) was hydrogenated for 2 h at room temperature and at normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50%
H
2 0; 0.5 g per g of starting material). The mixture was 35 filtered trough a pad of celite. The residue was washed (MeOH, WO 2011/015241 PCT/EP2009/060168 194 MeOH/CH 2 Cl 2 1:1, THF) . The combined filtrate and washings were concentrated to obtain a macrocyclic acid. 5 Procedure I I.1: Teoc deprotection with dioxane-HCl A solution of a macrocyclic Teoc-amine (1.5 mmol) in dioxane (18 mL) was treated with 4 M HCl in dioxane (18 mL) and stirred at room temperature for 4-16 h. The mixture was treated with 10 diethyl ether and filtered. The solid was washed with diethyl ether and dried i.v. to give the macrocyclic amine hydrochloride. 15 1.2: Teoc deprotection with TBAF in THF A solution of TBAF (1 M in THF, 3 equiv.) was added at 00C to a solution of a macrocyclic Teoc-amine (1.3 mmol) in THF (34 mL). Stirring at 00C to room temperature was continued for 3 h. The solution was distributed between CH 2 Cl 2 and H 2 0. The organic 20 phase was washed (H 2 0), dried (Na 2 SO4), filtered and concentrated to provide after FC the macrocyclic amine. Procedure J 25 A solution of a macrocyclic Boc-amine in dioxane (10 mL per g of starting material) was treated with 4 M HCl in dioxane (20 mL per g of starting material) and stirred at room temperature for 2 h. The mixture was filtered. The solid was washed with diethyl ether and dried i.v. to give the macrocyclic amine 30 hydrochloride. Procedure K A solution of a macrocyclic benzylcarbamate (0.9 mmol) in MeOH 35 (52 mL) was hydrogenated for 4 h at room temperature and at normal pressure in the presence of palladium hydroxide on WO 2011/015241 PCT/EP2009/060168 195 activated charcoal (moistened with 50% HO; 0.3 g) . The mixture was filtered trough a pad of celite. The residue was washed (MeOH). The combined filtrate and washings were concentrated to obtain the macrocyclic amine. 5 Procedure L Amide coupling L.1.1: with carboxylic acid anhydrides or acylchlorides 10 A solution of an amino macrocycle (free amine or hydrochloride; 0.09 mmol) in CH2Cl 9 (1 mL) was at 0 C subsequently treated with pyridine (10 equiv.) and the carboxylic acid anhydride (1.05-5 equiv.) or a carboxylic acid chloride (1.05-2.0 equiv.), respectively. The solution was stirred at room 15 temperature for 15 h. After the addition of MeOH (0.1 mL) the solution was stirred for 10 min and concentrated. The resulting crude product was coevaporated with toluene and purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to give an N-acylamino macrocycle. 20 L.1.2: with carboxylic acid and polymersupported carbodiimide A solution of an amino macrocycle (free amine or hydrochloride; 0.09 mmol), a carboxylic acid (1.2 equiv.), HOBt.H20 (1.2 25 equiv.) in CH 9 Cl 9 (1 mL) was treated with N-cyclohexyl carbodiimide-N'-methylpolystyrene (1.9 mmol/g; 1.5 equiv.) and i-Pr 2 NEt (3.0 equiv.) . The mixture was stirred for 15 h at room temperature. (Polystyrylmethyl)trimethylammonium bicarbonate (3.5 mmol/g; 3 equiv.) was added and stirring was continued for 30 1 h. The mixture was diluted with CH2Cl2/MeOH 9:1 (2 mL) and filtered. The polymer was washed twice with CHCl2/MeOH 8:2 (5 mL). The combined filtrate and washings were concentrated. Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded an N-acylamino 35 macrocycle WO 2011/015241 PCT/EP2009/060168 196 L.1.3: with a carboxylic acid and HATU A solution of an amino macrocycle (free amine or hydrochloride; 0.145 mmol), a carboxylic acid (2.0 equiv.), HATU (2.0 equiv.), 5 HOAt (2.0 equiv.) in DMF (2 mL) was treated with i-Pr2NEt (4.0 equiv.). The mixture was stirred for 15 h at room temperature. The solvent was removed. The residue was distributed between CHCl 3 and sat. aq. NaHCO 3 solution. The organic phase was washed (H 9 0) , dried (Na 2
SO
4 ), filtered and concentrated. 10 Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded an N-acylamino macrocycle. 15 L.2: with an amine and HATU A solution of a macrocyclic carboxylic acid (0.78 mmol), an amine (2.0 equiv.), HATU (2.0 equiv.), HOAt (2.0 equiv.) in DMF (6 mL) was treated with i-Pr 0 NEt (4.0 equiv.) . The mixture was stirred for 15 h at room temperature. The solvent was removed. 20 The residue was distributed between CHCl 3 and sat. aq. NaHCO 3 solution. The organic phase was washed (H20) , dried (Na 2 SO4), filtered and concentrated. Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocycle amide. 25 Procedure M N,N-Diethylamino macrocycles by reductive amination At 0*C NaBH(OAc), (5 equiv.) and acetaldehyde (1 mL) were added 30 to a solution of an the amino macrocycle (free amine or hydrochloride; 0.09 mmol) in THF (1 mL). The mixture was stirred at 0 0 C to room temperature for 15 h. The mixture was diluted with CHCl3 and washed with sat. aq. NaHCO3 soln. The organic phase was dried (Na2SO 4 ), filtered and concentrated. 35 Purification of the crude product by chromatography (FC, normal WO 2011/015241 PCT/EP2009/060168 197 phase or reversed phase prep. HPLC) afforded the diethylamino macocycle. 5 Procedure N Methylester cleavage A solution of the methylester (57 !Mol) in THF (1.5 mL) and MeOH (0.5 mL) was treated with H20 (0.5 mL) and lithium hydroxide monohydrate (3 equiv.) for 2 h at room temperature. 10 The mixture was acidified by addition of aqueous 1 M HCl and concentrated. The crude product was purified by prep. HPLC. 15 Synthesis of A-cl Fragments 1. Synthesis of (S)-5-allyl 1-benzyl 2-(5-fluoro-2-hydroxy-N methylbenzamido)pentanedioate (54) (Scheme 4) 20 Following procedure A (steps A.1-A.3), the reaction of 2 acetoxy-5-fluoro benzoic acid (2, 11.78 g, 59 mmol) and oxalylchloride (18 mL, 206 mmol)in dry CH 2 Cl 0 (516 mL) in the presence of DMF (50 pL) afforded 2-acetoxy-5-fluoro benzoyl chloride (52). 25 Reaction of acid chloride 52 with (S)-5-allyl 1-benzyl 2 (methylamino)pentanedioate hydrochloride (27'HCl, 15.0 g, 46 mmol) in THF (260 mL) in the presence of i-PrNEt (23 mL, 137 mmol) yielded the acetate 53 (19.35 g, 90%), which was treated with 3-dimethylamino-l-propylamine (23 mL, 185 mmol) in THF 30 (200 mL) to afford after aqueous workup (EtOAc, 0.1 M aq. HCl soln, sat. aq. NaCl soln) and after FC (hexane/EtOAc 8:2 to 7:3) the phenol 54 (14.4 g, 81%). Data of 54: C23H 24 FN0 6 (429.4). HPLC (30% CH 3 CN) Rt = 3.79 (87 %). LC-MS (method 9a): RL = 2.09, 430 ([M+H]-) 35 WO 2011/015241 PCT/EP2009/060168 198 2. Synthesis of (R)-5-allyl 1-benzyl 2-(5-fluoro-2-hydroxy-N methylbenzamido)pentanedicate (56) (Scheme 4) Following procedure A (steps A.1-A.3), the reaction of 2 5 acetoxy-5-fluoro benzoic acid (2, 13.0 g, 67 mmol) and oxalylchloride (20 mL, 233 mmol)in dry CH2Clz (585 mL) in the presence of DMF (50 pL) afforded 2-acetoxy-5-fluoro benzoyl chloride (52). Reaction of acid chloride 52 with (R)-5-allyl 1-benzyl 2 10 (methylamino)pentanedioate hydrochloride (29'HCl, 17.0 g, 52 mmol) in THF (280 mL) in the presence of i-Pr2NEt (27 mL, 156 mmol) yielded 55 (21.5 g, 88%), which was treated with 3 dimethylamino-l-propylamine (26 mL, 205 mmol) in THF (200 mL) to afford after aqueous workup (EtOAc, 0.1 M aq. HCl soln, sat. 15 aq. NaCl soln) and after FC (hexane/EtOAc 8:2 to 7:3) the phenol 56 (14.8 g, 75%). Data of 56: C 2 3
H
2 4 FN0 6 (429.4). HPLC (30% CH 3 CN) : Rt = 3.79 (89) LC-MS (method 9c): R- = 2.11, 430 ([M+H]) 20 3. Synthesis of (S)-allyl 2-(benzyloxycarbonylamino)-3-(3 hydroxy-N-methylbenzamido)propanoate (59) (Scheme 4) Following procedure A (steps A.1-A.3), the reaction of 3 acetoxybenzoic acid (3, 6.0 g, 33 mmol) and oxalylchloride (14 25 mL, 164 mmol) in dry diethyl ether (216 mL) in the presence of DMF (50 pL) afforded 3-acetoxybenzoyl chloride (57, 7.0 g, quant.). Reaction of 57 (7.0 g, 35 mmol) with (S)-allyl 2 (benzyloxycarbonylamino)-3-(methylamino)propanoate 30 hydrochloride (32*HCl, 10.5 g, 32 mmol) in CH 2 Cl2 (285 mL) in the presence of 2,4,6-collidine (12.8 mL, 96 mmol) yielded 58 (12.34 g, 82%). The acetate 58 (12.82 g, 28.2 mmol) was treated with 3 dimethylamino-1-propylamine (10.6 mL, 84.6 mmol) in THF (114 35 mL) to afford the phenol 59 (10.45 g, 90%).
WO 2011/015241 PCT/EP2009/060168 199 Data of 59: C 92
H
9 4
N
2 0 6 (412.4). HPLC (10% CH 3 CN): Rt = 3.91 (96). LC-MS (method 9a): Rt = 1.77, 413 ( [M+H]'). 5 4. Synthesis of (R)-allyl 2-(benzyloxycarbonylamino)-3-(3 hydroxy-N-methylbenzamido)propanoate (61) (Scheme 4) Following procedure A (steps A.1-A.3), the reaction of 3 acetoxybenzoic acid (3, 5.82 g, 32.3 mmol) and oxalylchloride (11.1 mL, 129 mmol) in dry diethyl ether (210 mL) in the 10 presence of DMF (50 pIL) afforded 3-acetoxybenzoyl chloride (57, 6.5 g, 100%). Reaction of 57 (6.5 g, 32.3 mmol) with (R)-allyl 2 (benzyloxycarbonylamino)-3-(methylamino)propanoate hydrochloride (36'HCl, 8.5 g, 26 mmol) in CHICl 2 (220 mL) in the 15 presence of 2,4,6-collidine (10.3 mL, 77.6 mmol) yielded 60 (10.73 g, 92%). The acetate 60 (15.46 g, 34 mmol) was treated with 3 dimethylamino-l-propylamine (12.8 mL, 102 mmol) in THF (140 mL) to afford the phenol 61 (12.92 g, 92%). 20 Data of 61: C2 2
H
2 4
N
2 06 (412.4) . LC-MS (method 2): R = 1.77 (98), 413 ([M+H]+). 5. Synthesis of (S)-allyl 2-(benzyloxycarbonylamino)-4-(3 25 hydroxy-N-methylbenzamido)butanoate (63) (Scheme 4) Following procedure A (steps A.1-A.3), the reaction of 3 acetoxybenzoic acid (3, 7.65 g, 43 mmol) and oxalylchloride (18.2 mL, 213 mmol) in dry CH 2 C1 (140 mL) in the presence of DMF (300 gL) afforded after 3 h at room temperature 3 30 acetoxybenzoyl chloride (57). Reaction of 57 thus obtained with (S)-allyl 2 (benzyloxycarbonylamino)-5-(methylamino)butanoate hydrochloride (40-HCl, 8.7 g, 28 mmol) in THF (140 mL) in the presence of i Pr 2 NEt (15 mL, 85 mmol) yielded 62 (8.1g, 61%).
WO 2011/015241 PCT/EP2009/060168 200 The acetate 62 (4.85 g, 10 mmol) was treated with 3 dimethylamino-l-propylamine (3.8 mL, 31 mmol) in THF (90 mL) to afford the phenol 63 (4.23 g, 95%). Data of 63: C2 3
H
2 36N0 (426.5) . LC-MS: (method 6): R, = 1.06 5 (99), 427 ([M+H]K). 6. Synthesis of (S)-allyl 2-(benzyloxycarbonylamino)-5-(3 hydroxy-N-methylbenzamido)pentanoate (65) (Scheme 4) 10 Following procedure A (steps A.1-A.3), the reaction of 3 acetoxybenzoic acid (3, 10 g, 58 mmol) and oxalylchloride (19 mL, 218 mmol) in dry CH 2 Cl, (450 mL) in the presence of DMF (500 pIL) afforded 3-acetoxybenzoyl chloride (57). Reaction of 57 thus obtained with (S)-allyl 2 15 (benzyloxycarbonylamino)-5-(methylamino)pentanoate hydrochloride (44'HCl, 17.3 g, 48 mmol) in THF (200 mL) in the presence of i-Pr2NEt (25 mL, 145 mmol) yielded 64 (12.08 g, 51%), which was treated with 3-dimethylamino-1-propylamine (9.3 mL, 75 mmol) in THF (240 mL) to afford after aqueous workup 20 (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat.- aq. NaCl soln) the phenol 65 (10.84 g, 98%). Data of 65: C2 4
H
2 qN 2
O
6 (440.5) . LC-MS (method 6): Rt = 1.15 (91), 441 ([M+H]K) 25 7. Synthesis of (S)-5-allyl 1-benzyl 2-(4-hydroxy-N methylbenzamido)pentanedioate (68) (Scheme 4) Following procedure A (steps A.1-A.3), the reaction of 4 acetoxybenzoic acid (4, 10.7 g, 59.5 mmol) and oxalylchloride 30 (17.7 mL, 206 mmol) in dry CH 2 C12 (350 mL) in the presence of DMF (50 pL) afforded 4-acetoxybenzoyl chloride (66). Reaction of 66 with (S)-5-allyl 1-benzyl 2 (methylamino)pentanedioate hydrochloride (27'HCl, 15.0 g, 46 mmol) in THF (250 mL) in the presence of i-Pr 2 NEt (23.3 mL, 137 35 mmol) yielded 67 (16.24 g, 78%).
WO 2011/015241 PCT/EP2009/060168 201 The treatment of 67 (15.2 g, 33.5 mmol) with 3-dimethylamino-1 propylamine (12.6 mL, 101 mmol) in THF (140 mL) afforded the phenol 68 (14.86 g, quant.; the product was contaminated with 9% EtOAc). 5 Data of 68: C 2 3H 25
NO
6 (411.4). LC-MS (method 9b): Rt = 1.96, 412 ([M+H] ). 8. Synthesis of (S)-allyl 2-(benzyloxycarbonylamino)-3-(5 10 hydroxy-N-methylnicotinamido)propanoate (71) (Scheme 4) A mixture of 5-hydroxy nicotinic acid (5, 3.5 g, 25.1 mmol) and acetic anhydride (23 mL, 243 mmol) was heated at 95 0 C for 45 min and cooled to room temperature. The mixture was filtered. The solid was washed (H,0, diethyl ether) and dried i.v. to 15 give 5-acetoxynicotinic acid (6; 3.76 g, 82%) (Scheme 1) 5-Acetoxynicotinic acid (6; 5.7 g, 31.5 mmol) was suspended in CHCl 3 (stabilized with amylene, 230 mL) . Oxalylchloride (9.0 mL, 105 mmol) was added followed by DMF (ca. 50 gL). The mixture was stirred at room temperature for 15 h, then 20 concentrated, coevaporated with dry CH2Cl 2 and dried i.v. to afford 5-acetoxynicotinoyl chloride (69). (S)-allyl 2 (benzyloxycarbonylamino)-3-(methylamino)propanoate hydrochloride (32, 8.6 g, 26.2 mmol) and THF (225 mL) were added. The mixture was cooled to 0 C. Et3N (13 mL, 92 mmol) was 25 slowly added. The mixture was stirred at 0 C to room temperature for 18 h. 3-dimethylamino-1-propylamine (9.9 mL, 78.6 mmol) was added and stirring at room temperature was continued for 2 h. The mixture was distributed between EtOAc and 1 M aq. NaH 2
PO
4 solution. The organic layer was separated, 30 washed (sat. aq. NaCl soln), dried (Na2SO 4 ), filtered and concentrated. FC (CH2Cl 2 /MeOH 19:1) afforded the phenol 71 (8.81 g, 81%). Data of 71: C 0 1H 23 N]0 6 (413.4). LC-MS (method 6): Rt = 0.94 (92), 414 ([M+H]K) 35 WO 2011/015241 PCT/EP2009/060168 202 9. Synthesis of allyl (2S)-2-[(benzyloxy)carbonyl]amino-3 [((2S)-2-[(tert-butoxycarbonyl)amino]-8-hydroxy-1,2,3,4 tetrahydro-2-naphthalenylcarbonyl) (methyl)aminoipropanoate 5 (72) (Scheme 4) A mixture of 10 (3.0 g, 9.76 mmol), HATU (5.57 g, 14.6 mmol), HOAt (1.99 g, 14.6 mmol) and 32'HCl (6.4 g, 19.5 mmol) were dissolved in DMF (113 mL). i-Pr 2 NEt (8.36 mL, 48.8 mmol) was added. The mixture was stirred at room temperature for 3 d. The 10 mixture was distributed between H 2 0 and EtOAc. The organic phase was dried (Na 2 SOI), filtered, and concentrated. FC (hexane/EtOAc 75:25 to 50:50) afforded 72 (2.58 g, 45%). Data of 72: C 3 nHa9N30 (581.3) . LC-MS (method 7): Rt = 1.27 (97), 582 ( [M+H] ) 15 10. Synthesis of 5-allyl 1-benzyl (2S)-2-[[(8-hydroxy-2 quinolinyl)carbonyl](methyl)amino]pentanedioate(75) (Scheme 4) 20 Following procedure A (steps A.1-A.3), the reaction of 8 Acetoxyquinoline-2-carboxylic acid (8, 2.22 g 9.6 mmol) and oxalylchloride (2.1 mL, 24 mmol) in dry CH 2 C1 2 (90 mL) (no addition of DMF) afforded after 2 h at room temperature acetoxyquinoline-2-carboxylic acid chloride (73). 25 Reaction of 73 with (S)-5-allyl 1-benzyl 2 (methylamino)pentanedioate hydrochloride (27'HCl, 2.3 g, 8.0 mmol) in CH 2 Cl2 (200 mL) in the presence of i-Pr2NEt (5.5 mL, 32 mmol) yielded after 2.5 h at room temperature and purification by FC (hexane/EtOAc gradient) 74 (3.03 g, 74%), which was 30 treated with 3-dimethylamino-l-propylamine (2.3 mL, 18 mmol) in THF (54 mL) to afford after aqueous workup (EtOAc, 1 M aq. HC1 soln, sat. aq. NaHCO 3 soln, sat.- aq. NaCl soln) the phenol 75 (2.79 g, 99%). Data of 75: C26H2 6
N
2 0 6 (462.5) . LC-MS (method 7): Rt = 1.29 (94), 35 463 ([M+H]K).
WO 2011/015241 PCT/EP2009/060168 203 11. Synthesis of N-allyl-3-hydroxy-N-methylbenzamide (77) (Scheme 4) Following procedure A (steps A.1-A.3), the reaction of 3 5 acetoxybenzoic acid (3, 23.7 g, 132 mmol) and oxalylchloride (45.3 mL, 527 mmol) in dry diethyl ether (800 mL) in the presence of DMF (100 jiL) afforded 3-acetoxybenzoyl chloride (57). Reaction of 57 thus obtained with N-allylmethylamine (10.1 ml, 10 105 mmol) in CHCl, (500 mL) in the presence of 2,4,6-collidine (42 mL, 316 mmol) yielded 76 (24 g, 98%). The acetate 76 (10.9 g, 46.7 mmol) was treated with 3 dimethylamino-l-propylamine (17.5 mL, 140 mmol) in THF (90 mL) to afford after aqueous workup (EtOAc, 1 M aq. HCl soln, sat. 15 aq. NaCl soln) the phenol 77 (9.0 g, 100%). Data of 77: C-H 13 NOQ (191.2). LC-MS (method 2): R- = 1.52 (99), 192 ([M+H]K). 20 12. Synthesis of (S)-5-allyl-l-benzyl 2-(3-mercapto-N methylbenzamido)pentanedicate (80) (Scheme 4) Acetic anhydride (0.46 mL, 4.86 mmol) was added at 0 0 C to a solution of 3-mercaptobenzoic acid (11, 250 mg, 1.62 mmol) in 1 25 M aqueous NaOH solution (5.0 mL, 5.0 mmol). The mixture was stirred at 0 0 C for 1 h. A precipitate was formed. The mixture was acidified by the addition of 1 M aqueous HCl solution and filtered. The solid was dried i.v. to afford 3 (acetylthio)benzoic acid (12; 280 mg, 88%). 30 Oxalyl chloride (0.34 mL, 3.97 mmol) was added to a mixture of 12 (260 mg, 1.33 mmol) and CHC1 3 (stabilized with amylene; 16 mL). DMF (7 tL) was added. The mixture was stirred at room temperature for 2 h. The volatiles were evaporated to afford 3 (acetylthio)benzoyl chloride (78).
WO 2011/015241 PCT/EP2009/060168 204 (S)-5-allyl 1-benzyl 2-(methylamino)pentanedioate hydrochloride (27'HCl, 434 mg, 1.33 mmol) and dry THF (5 mL) were added. The mixture was cooled to 0 0 C, followed by the addition of i-Pr2NEt (0.79 mL, 4.6 mmol). The mixture was stirred at room 5 temperature for 16 h and distributed between EtOAc and 1 M aqueous HCl solution. The organic phase was separated, dried (NaSO 4 ), filtered and concentrated. FC (hexane/EtOAc 2:1) afforded the acetate 79 (420 mg, 67%). At room temperature, a solution of 79 (246 mg, 0.52 mmol) in 10 degassed THF (3.6 mL) was treated with 3-dimethylamino-l propylamine (0.13 mL, 1.05 mmol) for 1 h. The mixture was distributed between EtOAc and 1 M aqueous HCl solution. The organic phase was separated, dried (Na2SO 4 ), filtered and concentrated. FC (hexane/EtOAc 2:1) afforded 80 (153 mg, 68%). 15 Data of 80: C, 3 H?5NOS (427.5): LC-MS (method 7): R, = 1.39 (84), 428 ([M+H]K) 20 Synthesis of c2-B Fragments 1. Synthesis of allyl N-2-[(2S,4S)-4-[(tert butoxycarbonyl)amino]-2-(hydroxymethyl)tetrahydro-lH-pyrrol-l 25 yl]-2-oxoethyl-N-methylcarbamate (81) (Scheme 5) A solution of (2-((allyloxycarbonyl) (methyl)amino)acetic acid (47, 8.0 g, 46 mmol) and aminoalcohol 13 (11.0 g, 51 mmol) in DMF (120 mL) was cooled to 0 0 C. 2,4,6-Collidine (11 mL, 82 mmol) was added followed by HATU (22 g, 58 mmol). The mixture 30 was stirred for 1 h at 0 0 C then for 16 h at room temperature followed by distribution between EtOAc and sat. aq. Na2CO, solution. The organic phase was washed (1 M aq. HCl soln, sat. aq. NaCl soln) , dried (NaSO 4 ), filtered and concentrated. FC (EtOAc/MeOH 100:0 to 95:5) afforded the amidoalcohol 81 (14.7 35 g, 86%).
WO 2011/015241 PCT/EP2009/060168 205 Data of 81: C- 7
H,
9
N
3 0 6 (371.4). HPLC (20% CH 3 CN): Rt = 2.94 (97). LC-MS (method 9c): Rt = 1.55; 743 ([2M+H]+), 372 ([M+H]) 5 2. Synthesis of allyl N-2-[(2S,4R)-4-[(tert butoxycarbonyl)amino]-2-(hydroxymethyl)tetrahydro-lH-pyrrol-l yl]-2-oxoethyl-N-methylcarbamate (82) (Scheme 5) Following procedure D, the reaction of the amnioalcohol 17'HCl (10.0 g, 39.6 mmol) and 2 10 ((allyloxycarbonyl) (methyl)amino)acetic acid (47, 15.1 g, 87 mmol) in DMF (100 mL) in the presence of HCTU (40.9 g, 98.9 mmol), Cl-HOBt (1.68 g, 9.89 mmol) and i-PrzNEt (33.6 mL, 198 mmol) afforded after FC (hexane/EtOAc 20:80 to 0:100) the corresponding amido ester intermediate (13.7 g) which was 15 saponified with lithium hydroxide monohydrate (3.28 g, 78.1 mmol) in THF (350 mL) and H 2 0 (90 mL) to yield the amidoalcohol 82 (8.89 g, 61%). Data of 82: C 7 H29N 3 6 (371.4) . LC-MS (method 9b) : Rt = 1.57; 372 ([M+H]*), 316, 272 ([M+H-Boc]), 156. 20 3. Synthesis of tert-butyl (3R)-4-{2 [[(allyloxy)carbonyl](methyl)amino]acetyl}-3 25 (hydroxymethyl)tetrahydro-1(2H)-pyrazinecarboxylate (84) (Scheme 5) Following procedure D, the reaction of (R)-tert-butyl 3 (hydroxymethyl)piperazine-l-carboxylate hydrochloride (83*HCl, 19.7 g, 78 mmol) and 3-((allyloxycarbonyl) (methyl)amino)acetic 30 acid (47, 30 g, 172 mmol) in DMF (188 mL) in the presence of HCTU (81.0 g, 195 mmol), Cl-HOBt (3.3 g, 19 mmol) and i-Pr 2 NEt (67 mL, 390 mmol) afforded after FC (EtOAc) the corresponding amido ester intermediate (40 g) which was saponified with lithium hydroxide monohydrate (9.5 g, 228 mmol) in THF (1020 35 mL) and H20 (245 mL) to yield after FC (EtOAc) amidoalcohol 84; 22.8g, 79%).
WO 2011/015241 PCT/EP2009/060168 206 Data of 84: C- 7
H,
9 N30 6 (371.4). LC-MS (method 7): Rt = 0.99 (93), 372 ( [M+H] ). 5 4. Synthesis of benzyl N-((lS)-l-[(2S,4S)-4-[(tert butoxycarbonyl)amino]-2-(hydroxymethyl)tetrahydro-lH-pyrrol-l yl]carbonyl-3-butenyl)carbamate (85) (Scheme 5) Aminoalcohol-hydrochloride 13'HCl (3.7 g, 14.7 mmol) was added to a solution of acid 51 (5.22 g, 14.7 mmol) in DMF (80 ml). 10 The mixture was cooled to 0 C. HATU (7.0 g, 18.4 mmol) and 2,4,6-collidine (3.51 ml, 26.4 mmol) were added. The solution was stirred at 0 0 C to room temperature for 17 h, followed by distribution between EtOAc and sat. aq. Na 2
CO
3 solution. The organic phase was washed (1 M aq. HCl soln, sat. aq. NaHCO 3 15 soln, sat. aq. NaCl soln), dried (Na2SO 4 ), filtered and concentrated. FC (hexane/EtOAc 30:70 to 20:80) afforded the amidoalcohol (85, 5.78 g, 88%) Data of 85: C2 3
H
3 3
N
3 6 (447.5). LC-MS (method 2): Rt = 1.92 (92), 448 ([M+H]K) 20 5. Synthesis of allyl N-3-[(2S,4R)-4-[(tert butoxycarbonyl)amino]-2-(hydroxymethyl)tetrahydro-lH-pyrrol-l yl]-3-oxopropyl-N-methylcarbamate (86) (Scheme 5) 25 Following procedure D, the reaction of aminoalcohol 17'HCl (7.5 g, 30 mmol) and 3-((allyloxycarbonyl) (methyl)amino)propanoic acid (49, 12.3 g, 66 mmol) in DMF (77 mL) in the presence of HCTU (31.0 g, 75.0 mmol), Cl-HOBt (1.27 g, 7.5 mmol) and i Pr2NEt (25.6 mL, 150 mmol) afforded after FC (CHCl 2 /MeOH 100:0 30 to 97:3) the corresponding amido ester intermediate (17.1 g) which was saponified with lithium hydroxide monohydrate (3.8 g, 90 mmol) in THF (388 mL) and H 2 0 (105 mL) to yield the amidoalcohol 86 (10.48 g, 86%). Data of 86: CI8H 31 N30s (385.4) . HPLC (10% CH 3 CN): Rt = 3.49 (88). 35 LC-MS (method 9a) : R- = 1.62; 386 ([M+H]K), 330 ([M+H-tBu]), 286 ([M+H-Boc]+).
WO 2011/015241 PCT/EP2009/060168 207 5 Core 01: Synthesis of Ex.1 (Scheme 6) Synthesis of the Mitsunobu product 87 To a solution of 54 (350 mg, 0.82 mmol), 16 (590 mg, 1,7 mmol) and PPh 3 (1069 mg, 4.08 mmol) in dry degassed CHCl 3 (11 mL) was 10 added ADDP (1028 mg, 4.08 mmol) in one portion at 0 C, under a N? atmosphere. The resulting mixture was stirred for 16 h at room temperature. The mixture was filtered and the slurry washed further with diethyl ether. The combined filtrates were concentrated in vacuo. The crude residue was purified by FC 15 (CHQCl 2 /EtOH 100:0 to 99:1) to afford 87 (1.05 g, contains triphenylphosphine oxide; used in the next step without further purification). 20 Synthesis of the amino acid 88 Following procedure B.2, the reaction of 87 (441 mg, contaminated with triphenylphosphine oxide, ca 0.5 mmol), 1,3 dimethylbarbituric acid (219 mg, 1.4 mmol) and Pd(PPh3) 4 (34 mg) in EtOAc/CH 2 Cl 2 (55:45, 10 mL) yielded after 1,5 h and 25 subsequent FC (CH2Cl 2 /MeOH 100:0 to 80:20) amino acid 88 (267 mg, 72%). Data of 88: C 3
H
42 FNOSi (631.7) . LC-MS (method 9a) Rt = 2.02, 632 ([M+H]K). HPLC (30% CH 3 CN) : Rt = 3.41 (96). 30 Synthesis of the macrolactam Ex.1 According to procedure F.1.1 the amino acid 88 (75 mg, 0.12 mmol) in dry CH>C1 2 (6 mL) was added within 4 h to T3P (50% in EtOAc, 0.21 mL, 0.36 mmol) and i-Pr 2 NEt (0.1 mL, 0.59 mmol) in 35 dry CH Cl2 (6 mL) to give after FC (CH Cl,/MeOH 100:0 to 96:4) the macrolactam Ex.1 (45 mg, 61%).
WO 2011/015241 PCT/EP2009/060168 208 Data of Ex.1: C 31
H,
0
FN
3 0 7 Si (613.7) . LC-MS (method 7): Rt = 1.45 (41), 614 ( [M+H]+) ; 1.47 (44), 614 ( [M+H]+) H-NMR (DMSO-dG) : complex spectrum, several isomers; 7.45-7.01 (m, 8 H), 6,78-6.58 (2 m, 1 H), 5.42-5.06 (m, 3 H), 4.50-3.50 5 (several m, 7 H), 3.30-1.40 (several m, 7 H), 2.84, 2.70, 2.66 (s, 3 H),0.97-0.82 (m, 2 H), 0.03, 0.02, 0.00 (s 9 H). 10 Core 02: Synthesis of Ex.2 (Scheme 11) Synthesis of the protected macrolactam Ex.2 A solution of T3P (50% in EtOAc, 0.75 mL, 1.27 mmol) and i Pr 2 NEt (0.36 mL, 2.2 mmol) in dry CH 2 Cl2 (20 mL) was added 15 within 2 h to a solution of the amino acid 98 (250 mg, 0.43 mmol) in dry CH 2 Cl, (730 mL) . The solution was stirred at room temperature for 20 h, followed by extraction with sat. aq. Na2COr solution. The organic phase was dried (Na 2
SO
4 ), filtered and concentrated. FC (CH 2 Cl2/MeOH 100:0 to 95:5) afforded Ex.2 20 (187 mg, 77%). Data of Ex.2: C 3 0H36FN 3 0 7 (569.6) LC-MS (method 7): Rt = 1.35 (62), 570 ([M+H]K); 1.39 (15), 570 ([M+H]K) 'H-NMR (DMSO-d 6 ) : complex spectrum, several isomers; 7.46-7.30 (m, 5 H), 7.27-7.06 (m, 2 H), 6.98-6.67 (4 dd, 1 H), 5.54-5.06 25 (m, 3 H), 4.68-3.48 (m, 6 H), 3.05-1.98 (m 10 H; s at 2.82, 2.69, 2.64), 1.44-1.41 (3 s, 9 H). 30 Core 03: Synthesis of Ex.3, Ex.4, and Ex.5 (Scheme 7) Synthesis of the Mitsunobu product 89 WO 2011/015241 PCT/EP2009/060168 209 Following procedure E.1.1, the reaction of phenol 54 (7.8 g, 18 mmol), alcohol 81 (16 g, 43 mmol), DEAD (40% in toluene, 37 mL, 82 mmol) , and PPh 3 (21 g, 80 mmol) in dry benzene (250 mL) afforded after FC (CH2Cl 2 /EtOH 100:0 to 95:5) the protected 5 amino acid 89 (15.9 g, contaminated with ca. 30% triphenylphosphine oxide; used in the next step without further purification). 10 Synthesis of the amino acid 90 Following procedure E.2, the reaction of 89 (9.6 g, contaminated with triphenylphosphine oxide, ca 9 mmol), 1,3 dimethylbarbituric acid (5.0 g, 32.0 mmol) and Pd(PPh3) 4 (0.4 g) in EtOAc/CH 2 Cl2 (55:45, 266 mL) yielded after 1,5 h and 15 after FC (CH 2 Cl 2 /MeOH 90:10 to 50:50) amino acid 90 (4.34 g, 76%). Data of 90: C 23
H
4 3FN 4 Oq (658.7). HPLC (10% CH3CN): Rt = 3.87 (99). LC-MS (method 9a) : R = 1.77, 659 ( [M+H]') 20 Synthesis of the protected macrolactam Ex.3 According to procedure F.1.2, the amino acid 90 (2.5 g, 3.80 mmol)in dry DMF (50 mL) was treated with FDPP (2.51 g, 6.53 25 mmol) in DMF (400 mL) to afford after FC (EtOAc/MeOH 100:0 to 95:5) the macrolactam Ex.3 (2.29 g, 94%). Data of Ex.3: C3 3 HL]FN40s (640.7) . HPLC (30% CH 3 CN) : Rt = 3.20 (96). LC-MS (method 9c) : Rt = 2.06, 641 ([M+H]) . H-NMR (CDCl): 7.45-7.32 (m, 5 H), 7.06 (m, 1 H), 6.94-6.88 (m, 2 H), 30 5.57 (dd, J = 2.8, 12.6, 1 H), 5.42 (br. m, 1 H), 5.26 (d, J = 12.2, 1 H), 5.15 (d, J = 12.2, 1 H), 4.90 (dd, J = 2.5, 11.0, 1 H), 4.34 (d, J = 17.2, 1 H), 4.35-4.11 (m, 3 H), 3.82 (br. t, J ca. 8.5, 1 H), 3.65 (d, J = 17.3, 1 H), 3.29 (t, J ca 8.8, 1 H), 3.14 (s, 3 H), 2.65 (s, 3 H), 2.51-1.98 (several m, 5 H), 35 1.76 (td, J = 8.2, 12.7, 1 H), 1.36 (s, 9 H).
WO 2011/015241 PCT/EP2009/060168 210 Synthesis of the acid Ex.4: According to procedure H, ester Ex.3 (2.0 g, 3.1 mmol) was hydrogenated in MeOH (120 mL)/THF (40 mL) in the presence of 5 the catalyst (1 g) for 2 h to afford Ex.4 (1.68 g, 97%). Data of Ex.4: C 26
H
3 5FN 4 0 8 (550.6) . HPLC (5% CH 3 CN) P, = 3.60 (86). LC-MS: (method 9c): Rt = 1.53; 551 ([M+H]), 451 ( [M+H Boc]) 10 Synthesis of the amine Ex.5: According to procedure J, ester Ex.3 (100 mg, 0.16 mmol) in dioxane (3 mL) was treated with 4 M HCl-dioxane (3 mL) to afford Ex.5-HC1 (100 mg, quant.) 15 Data of Ex.5*HCl: C 2 sH33FN 4 06'HCl (540.6, free base) . LC-MS: (method 9c): RL = 1.44, 541 ([M+H]-). 20 Core 04: Synthesis of Ex.56 and Ex.57 (Scheme 8) Synthesis of the Mitsunobu product 91 Following procedure E.1.1 the reaction of phenol 54 (8.0 g, 19 mmol), alcohol 82 (16.0 g, 43 mmol), DEAD (40% in toluene, 38 25 mL, 84 mmol) , and PPh3 (22 g, 84 mmol) in dry benzene (260 mL) afforded after FC the protected amino acid 91 (33.5 g, contaminated with triphenylphosphine oxide. The material was used in the next step without further purification). 30 Synthesis of the amino acid 92 Following procedure E.2, the reaction of 91 (33.5 g, impure material), 1,3-dimethylbarbituric acid (16 g, 102 mmol) and Pd(PPh) 4 (0.2 g) in EtOAc/CH 2 Cl 2 (45:55, 340 mL) yielded after 35 3 h and after FC (CH2Cl2/EtOH 100:0 to 70:30 then CHCl2/MeOH WO 2011/015241 PCT/EP2009/060168 211 90:10 to 70:30) amino acid 92 (4.8 g, 39% over the two steps, based on phenol 54). Data of 92: C 3 3
H
4 3
FN
4 0 9 (658.7). HPLC (10% CH3CN): Rt = 3.80 (95). LC-MS (method 9c): R- = 1.81, 659 ([M+H]K) 5 Synthesis of the protected macrolactam Ex.56 According to procedure F.1.1, amino acid 92 (3.8 g, 5.80 mmol) in dry CHCl- (40 mL) was treated with T3P (50% in EtOAc, 6.8 10 mL, 12 mmol) and i-Pr2NEt (4.0 mL, 23 mmol) in dry CH 2 C1 2 (510 mL) to afford after FC (EtOAc/MeOH 100:0 to 95:5) the macrolactam Ex.56 (3.23 g, 87%). Data of Ex.56: C3 3
H
41
FN
4 03 (640.7). HPLC (30% CH 3 CN): Rt = 3.49 (88). LC-MS (method 9c) : R = 2.02, 641 ([M+H]K) . H-NMR 15 (CDC1 3 ): 7.41-7.32 (m, 5 H), 7.04 (m, 1 H), 6.94-6.83 (m, 2 H), 5.54 (dd, J = 3.0, 12.7, 1 H), 5.25 (d, J = 12.2, 1 H), 5.14 (d, J = 12.2, 1 H), 4.89 (dd, J = 2.1, 11.0, 1 H), 4.63 (br. m, 1 H), 4.39-4.10 (m, 4 H), 3.79-3.64 (m, 2 H), 3.49 (br. m, 1 H), 3.12 (s, 3 H), 2.64 (s, 3 H), 2.51-2.36 (m, 2 H), 2.23-1.98 20 (m, 4 H),1.44 (s, 9 H). Synthesis of the acid Ex.57: According to procedure H, the ester Ex.56 (2.25 g, 3.5 mmol) 25 was hydrogenated in MeOH (120 mL)/THF (40 mL) in the presence of the catalyst (1.1 g) for 2 h to afford - after washing of the filtration residue with warm (50'C) MeOH/THF 3:1-the acid Ex.57 (1.9 g, 98%). Data of Ex.57: C 26 Ha 0
FN
4 O, (550.6). HPLC LC-MS: (method 2): R = 30 1.54 (82), 551 ( [M+H]K). 35 Core 05: Synthesis of Ex.85 and Ex.86 (Scheme 9) WO 2011/015241 PCT/EP2009/060168 212 Synthesis of the Mitsunobu product 93 Following procedure E.1.1, the reaction of phenol 56 (6.6 g, 15 mmol), alcohol 81 (13 g, 35 mmol), DEAD (40% in toluene, 32 mL, 69 mmol) , and PPh 3 (18 g, 69 mmol) in dry benzene (220 mL) 5 afforded after FC (CH 2 Clo/MeOH 100:0 to 94:6) the protected amino acid 93 (34.5 g, contaminated with triphenylphosphine oxide and diethyl hydrazine-1,2-dicarboxylate; acceptable for the use in the next step without further). 10 Synthesis of the amino acid 94 Following procedure E.2, the reaction of 93 (34.5 g, impure material), 1,3-dimethylbarbituric acid (17 g, 106 mmol) and Pd(PPh 3
)
4 (0.1 g) in EtOAc/CH 2 Cl 2 (55:45, 350 mL) yielded after 15 3 h and after FC (CH 2 Cl 2 /EtOH 100:0 to 70:30 then CH 5 Cl 2 /MeOH 90:10 to 70:30) the amino acid 94 (5.6 g, 55% over the two steps, based on phenol 56). Data of 94: C 3 3
H
4 3
FN
4 0 9 (658.7). HPLC (10% CH3CN): Rt = 3.79 (96). LC-MS (method 9c) : R = 1.77, 659 ([M+H]) 20 Synthesis of the protected macrolactam Ex.85 According to procedure F.1.1, amino acid 94 (2.75 g, 4.2 mmol) in dry CH2C1 2 (35 mL) was treated with T3P (50% in EtOAc, 4.9 25 mL, 8.3 mmol) and i-Pr 2 NEt (2.9 mL, 17 mmol) in dry CH 2 Cl 2 (355 mL) to yield after FC (EtOAc/MeOH 100:0 to 95:5) macrolactam Ex.85 (2.47 g, 92%). Data of Ex.85: C,3H 41
FN
4 0s (640.7). HPLC (30% CH 3 CN): Rt = 3.52 (96). LC-MS (method 9c) : Rt = 2.06; 641 ( [M+H]) , 541 ([M+H 30 Boc]). 'H-NMR (CDCl 3 ) : two isomers, ratio 85:15, 7.42-7.31 (m, 5 H), 7.08-6.77 (m, 3 H), 5.33 (d, J = 8.3, 1 H), 5.23 (d, J = 12.2, 1 H), 5.17 (d, J = 12.1, 1 H), 4.84 (dd, J = 2.9, 8.9, 1 H), 4.37-4.25 (m, 3 H), 4.11 (dd, J = 4.2, 12.0, 1 H), 3.89 (t, J = 8.3, 1 H), 3.80 (d, J = 8.9, 1 H), 3.61 (d, J = 17.1, 1 H), 35 3.16 (t, J = 9.1, 1 H), 3.13 (s, 2.55 H, NCH of major isomer), 3.03 (s, 0.45 H, NCH 3 of minor isomer), 2.98 (s, 2.55 H, NCH 3 WO 2011/015241 PCT/EP2009/060168 213 of major isomer), 2.87 (0.45 H, NCH 3 of minor isomer), 2.64 2.41 (m, 2 H), 2.27-2.09 (m, 1 H), 1.98-1.83 (m, 2 H), 1.79 1.66 (m, 2 H), 1.45 (s, 7.65 H, Boc, major isomer), 1.35 (s, 1.35 H, Boc, minor isomer). 5 Synthesis of the acid Ex.86: According to procedure H, ester Ex.85 (2.0 g, 3.1 mmol) was hydrogenated in MeOH (120 mL) / THF (40 mL) in the presence of 10 the catalyst (1 g) for 2 h to afford - after washing of the filtration residue with warm (50'C) MeOH/TFH 3:1 - the acid Ex.86 (1.67 g, 97%). Data of Ex.86: C21H35FN 4 0s (550.6) . LC-MS: (method 3) : P7 = 1.10 (83), 551 ( [M+H]K); 1.17 (15), 551 ( [M+H]K) 15 Core 06: Synthesis of Ex.104 and Ex.105 (Scheme 10) 20 Synthesis of the Mitsunobu product 95 Following procedure E.1.2, the reaction of phenol 56 (13.1 g, 30.5 mmol), alcohol 82 (13.6 g, 36.6 mmol), and CMBP (14.7 g, 61 mmol) in dry toluene (500 mL) afforded after FC 25 (hexane/EtOAc 50:50 to 30:70) the protected amino acid 95 (16 g, 67%). Synthesis of the amino acid 96 30 Following procedure E.2, the reaction of 95 (16.0 g, 20 mmol), 1,3-dimethylbarbituric acid (8 g, 49 mmol) and Pd(PPh) 4 (0.1 g) in EtOAc/CH 2 Cl 2 (55:45, 220 mL) yielded after 3 h and after FC (CH2Cl 2 /EtOH 100:0 to 70:30 then CH2Cl,/MeOH 90:10 to 70:30) amino acid 96 (11 g, 81%). 35 Data of 96: C 3 3
H
4 3
FN
4 09 (658.7). LC-MS (method 2): Rt = 1.63 (97), 659 ([M+H]K).
WO 2011/015241 PCT/EP2009/060168 214 Synthesis of the protected macrolactam Ex.104 According to procedure F.1.1, amino acid 96 (4.0 g, 6.1 mmol) 5 in dry CH2C12 (40 mL) was treated with T3P (50% in EtOAc, 7.2 mL, 12.1 mmol) and i-Pr2NEt (4.2 mL, 24.3 mmol) in dry CH2C2 (1160 mL) to give after FC (CH 5 Cl/MeOH 100:0 to 95:5) macrolactam Ex.104 (2.32 g, 60%). Data of Ex.104: C3 3
H
4
!FN
4 0 8 (640.7) . LC-MS (method 7): R- = 1.21 10 (47), 641 ([M+H]+); 1.24 (53), 641 ([M+H]). 'H-NMR (DMSO-de): complex spectrum, mixture of isomers, 7.44-6.65 (m, 9 H), 5.32 5.05 (m, 2 H), 4.70-3.30 (several m, 9 H), 2.92 (s, NCH 3 of major isomer), 2.84 (s, NCH 3 of major isomer), 2.30-1.70 (several m, 6 H), 1.40, 1.38 (2 s, 9 H). 15 Synthesis of the acid Ex.105: According to procedure H, ester Ex.104 (2.15 g, 3.3 mmol) was hydrogenated in MeOH (215 mL) in the presence of the catalyst 20 (1.07 g) for 4 h to afford acid Ex.105 (1.72 g, 93%). Data of Ex.105: C> 6
H
35
FN
4 0 (550.6) . LC-MS: (method 7): Rt = 0.91 (45), 551 ([M+H]); 0.95 (38), 551 ([M+H]). 25 Core 07: Synthesis of Ex.115 and Ex.116 (Scheme 11) Synthesis of the Mitsunobu product 97 30 A mixture of the phenol 54 (6.42 g, 14.9 mmol), alcohol 22 (4.04 g, 13.5 mmol), and PPh 2 (9.73 g, 37.1 mmol) was dried i.v. for 15 min. and dissolved in dry, degassed chloroform (130 mL). The solution was cooled to 0 0 C. A solution of ADDP (9.36 g, 37.1 mmol) in chloroform (20 mL) was slowly added. The 35 mixture was stirred at room temperature for 3 h followed by the addition of more 22 (4.04 g, 13.5 mmol) and PPh 3 (5.97 g, 22.8 WO 2011/015241 PCT/EP2009/060168 215 mmol) in chloroform (20 mL). The mixture was cooled to 0 0 C. A solution of ADDP (5.74 g, 22.7 mmol) in chloroform (20 mL) was slowly added. The solution was stirred at room temperature for 16 h and concentrated. The residue was suspended in diethyl 5 ether and filtered. The solid was washed with diethyl ether. The combined filtrate and washings were concentrated. FC
(CH
9 Cl 2 /EtOAc 10:1) gave 97 (7.73 g, 73%). 10 Synthesis of the amino acid 98 Following procedure B.2, the reaction of 97 (7.72 g, 11 mmol), 1,3-dimethylbarbituric acid (4.1 g, 26.0 mmol) and Pd(PPh 3
)
4 (0.63 g) in EtOAc/CH 2 Cl 2 (53:47, 190 mL) yielded after 2 h and after FC (EtOAc, then CH 2 Cl2/MeOH 95:5 to 90:10) amino acid 98 15 (4.31 g, 67%). Data of 98: C 30
H
38
FN
3 0 8 (587.6). HPLC (10% CH 3 CN) : RL = 3.86 (84) LC-MS (method 9a) : R- = 1.76; 588 ([M+H]K), 488 ([M+H-Boc]) 20 Synthesis of the Alloc protected amino acid 99 Following procedure C.1, the reaction of the amino acid 98 (4.3 g, 7.3 mmol), allyl choroformate (0.86 mL, 8.0 mmol) and Na 2
CO
3 (1.2 g, 11 mmol) in dioxane (62 mL) and H20 (60 mL) gave acid 99 (5.07 g, 100%). 25 Synthesis of the protected diamide 100 Following procedure C.2, the acid 99 (4.9 g, 7.3 mmol) was reacted with sarcosine allylester p-toluenesufonate (46.p-TsOH, 30 2.6 g, 8.8 mmol), HOAt (1.5 g, 11 mmol), HATU (4.2 g, 11 mmol) and i-Pr2NEt (6.2 mL, 36 mmol) in DMF (75 mL) to afford the protected amino acid 100 (4.37 g, 76%). Data of 100: C 40
H
0
FN
4 0 1 (782.8) . HPLC (50% CH 3 CN) : R= 3.56 (99). LC-MS (method 9a) : Rt = 2.45; 783 ( [M+H]K), 683 ([M+H 35 Boc]).
WO 2011/015241 PCT/EP2009/060168 216 Synthesis of the deprotected amino acid 101 Following procedure C.3, the reaction of the protected amino acid 100 (4.36 g, 5.6 mmol), 1,3-dimethylbarbituric acid (2.1 5 g, 13 mmol) and Pd(PPh 3
)
4 (0.32 g) in EtOAc/CH 2 Cl2 (45:55, 106 mL) yielded amino acid 101 (3.46 g, 93%). Data of 101: C 3 3
H
4 3 FN40 (658.7). LC-MS (method 9b): Rt = 1.74; 659 ( [M+H]K), 559 ([M+H-Boc]). 10 Synthesis of the protected macrolactam Ex.115 According to procedure F.1.1, amino acid 101 (3.44 g, 5.2 mmol) in dry CH 2 C1 2 (50 mL) was treated with T3P (50% in EtOAc, 6.2 mL, 10 mmol) and i-Pr 2 NEt (3.6 mL, 21 mmol) in dry CH 2 C1 2 (470 15 mL) to give after FC (CH 2 Cl2/MeOH 95:5) macrolactam Ex.115 (2.95 g, 90%). Data of Ex.115: C3H 4 1FN 4 08 (640.7) . HPLC (20% CH 3 CN) : R, = 4.05 (93). LC-MS (method 9c) : Rt = 2.08; 641 ([M+H]K) . -H-NMR (DMSO d 6 ): complex spectrum, mixture of isomers, 7.38 (s, 5 H), 7.35 20 6.95 (several m, 2 H), 6.81-6.72 (several m, 0.4 H), 6.64 (dd, J = 3.1, 8.2, 0.25 H), 6.39 (dd, J = 3.2, 7.7, 0.25 H), 6.30 (dd, J = 3.3, 8.2, 0.1 H), 5.37-4.99 (m, 3 H), 4.60-3.60 (several m, 9 H), 3.20-2.60 (several m and s, 8 H), 2.40-1.70 (several m, 4 H), 1.45, 1.43, 1.42, 1.38 (4 s, Boc). 25 Synthesis of the acid Ex.116: According to procedure H, the ester Ex.115 (1.2 g, 1.9 mmol) was hydrogenated in MeOH (120 mL) in the presence of the 30 catalyst (0.6 g) for 2 h to afford the acid Ex.116 (1.02 g, 99%). Data of Ex.116: C2 6
H
35
FN
4 0 8 (550.6) . HPLC (10% CH 3 CN) : R = 3.47 (20), 3.55 (75) . LC-MS: (method 9c) : Rt = 1.53, 1.58; 551 ([M+H]) 35 WO 2011/015241 PCT/EP2009/060168 217 Core 08: Synthesis of Ex.132 and Ex.133 (Scheme 12) 5 Synthesis of the Mitsunobu product 102 Following procedure E.1.2, the reaction of phenol 56 (2.0 g, 4.7 mmol), alcohol 84 (2.08 g, 5.6 mmol), and CMBP (2.25 g, 9.3 mmol) in dry toluene (80 mL) afforded after 3 h and after FC (hexane/EtOAc 1:1 to 1:2) the protected amino acid 102 (2.06 g, 10 56%). Synthesis of the amino acid 103 Following procedure E.2, the reaction of 102 (2.05 g, 2.6 15 mmol), 1,3-dimethylbarbituric acid (1.0 g, 6.3 mmol) and Pd(PPh) 4 (0.15 g) in EtOAc/CH2Cl2 (55:45; 45 mL) yielded after 2 h and after FC (EtOAc, then CH 2 Cl 2 /MeOH 95:5 to 70:30) amino acid 103 (1.45 g, 85%). Data of 103: C33H 43
FN
4 0 (658.7) . HPLC (5% CH,3CN) : R = 4.04 (97) 20 LC-MS (method 9c) : R_ = 1.87, 659 ([M+H]+). Synthesis of the protected macrolactam Ex.132 According to procedure F.1.1, the amino acid 103 (1.44 g, 2.19 25 mmol) in dry CH 2 Cl 2 (40 mL) was treated with T3P (50% in EtOAc, 2.6 mL, 4.37 mmol) and i-Pr 2 NEt (1.5 mL, 8.74 mmol) in dry
CH
2 Cl2 (170 mL) to give after FC (CH 2 Cl2/MeOH 95:5) the macrolactam Ex.132 (1.36 g, 96%). Data of Ex.132: C33H 4 FN40 (640.7). LC-MS (method 2): R = 1.93 30 (100), 641 ( [M+H]+) ; LC-MS (method 9c) : R = 2.12, 641 ( [M+H]) 'H-NMR (DMSO-d) : complex spectrum, mixture of isomers, 7.38 (s, 5 H), 7.35-6.99 (several m, 2 H), 6.85-6.73 (several m, 0.4 H), 6.65 (dd, J = 3.1, 8.2, 0.25 H), 6.39 (dd, J = 3.1, 7.9, 0.25 H), 6.30 (dd, J = 3.3, 8.1, 0.1 H), 5.37-4.99 (m, 3 H), 35 4.6-3.6 (several m, 9 H), 3.2-2.6 (several m and s, 8 H), 2.4 1.7 (several m, 4 H), 1.45, 1.43, 1.41, 1.38 (4 s, Boc).
WO 2011/015241 PCT/EP2009/060168 218 Synthesis of the acid Ex.133: According to procedure H, ester Ex.132 (1.13 g, 1.7 mmol) was 5 hydrogenated in MeOH (110 mL) in the presence of the catalyst (0.56 g) for 4 h to afford acid Ex.133 (0.92 g, 94%). Data of Ex. 133: C 26 H3 5
FN
4 0 8 (550.6) . HPLC (5% CH 3 CN): Rt = 3.65 (27), 3.72 (71). LC-MS: (method 9c): Rt = 1.53, 551 ( [M+H]) 1.57, 551 ([M+H]) 10 Core 09: Synthesis of Ex.142 and Ex.143 (Scheme 13) 15 Synthesis of the Mitsunobu product 104 Following procedure E.1.2, the reaction of the phenol 54 (3.1 g, 7.2 mmol), alcohol 86 (3.34 g, 8.7 mmol), and CMBP (3.49 g, 14.4 mmol) in dry toluene (123 mL) afforded after 3 h and after 20 FC (hexane/EtOAc 1:1 to 1:2) the protected amino acid 104 (4.11 g, 71%). Synthesis of the amino acid 105 25 Following procedure E.2, the reaction of 104 (4.07 g, 5.1 mmol), 1,3-dimethylbarbituric acid (1.9 g, 12 mmol) and Pd(PPh 3
)
4 (0.3 g) in EtOAc/CH 2 Cl 2 (45:55, 90 mL) yielded after 2 h and after FC (EtOAc, then CH2Cl2/MeOH 95:5 to 70:30) the amino acid 105 (3.19 g, 93%). 30 Data of 105: C 3 4
H
4 5
FN
4 09 (672.7) . HPLC (5% CH3CN) : R = 3.96 (88). LC-MS (method 9c): R- = 1.83, 673 ([M+H]). Synthesis of the protected macrolactam Ex.142 35 According to procedure F.1.1, amino acid 105 (2.4 g, 3.6 mmol) in dry CH2Cl2 (40 mL) was treated with T3P (50% in EtOAc, 4.2 WO 2011/015241 PCT/EP2009/060168 219 mL, 7.1 mmol) and i-Pr 2 NEt (2.4 mL, 14.2 mmol) in dry CH 2 Cl2 (300 mL) to give after FC (CH 2 Cl 2 /MeOH 95:5) the macrolactam Ex.142 (1.92 g, 82%). Data of Ex.142: C3 4
H
43
FN
4 0 (654.7). HPLC (30% CH 3 CN): R, = 3.50 5 (89) . LC-MS (method 9b): Rt = 2.01; 655 ( [M+H]) , 599 ( [M+H tBu]), 555 ([M+H-Boc]+). 'H-NMR (DMSO-d): complex spectrum, mixture of isomers, 7.41-7.38 (m, 5 H), 7.37-7.14 (m, 3 H), 6.80-6.67 (m, 1 H), 5.45-5.13 (m, 3 H), 4.60-3.30 (several m, 8 H), 3.10-2.50 (several m and s, 8 H), 2.50-1.80 (several m, 6 10 H), 1.39, 1.38, 1.36 (3 s, Boo). Synthesis of the acid Ex.143: According to procedure H, ester Ex.142 (1.07 g, 1.6 mmol) was 15 hydrogenated in MeOH (100 mL) in the presence of the catalyst (0.53 g) for 4 h to afford acid Ex.143 (0.92 g, 99%). Data of Ex.143: C 2 7 H3 7 F140 (564.6) . LC-MS: (method 2): Rt = 1.54 (91), 565 ([M+H]). 20 Core 10: Synthesis of Ex.164 and Ex.165 (Scheme 14) Synthesis of the Mitsunobu product 106 25 Following procedure B.1.2, the reaction of phenol 63 (4.2 g, 9.8 mmol), alcohol 16 (4.4 g, 13 mmol), and CMBP (4.8 g, 20 mmol) in dry toluene (120 mL) afforded after 4 h and FC (hexane/EtOAc 50:50) the protected amino acid 106 (6.37 g, 86%). 30 Synthesis of the amino acid 107 Following procedure B.2, the reaction of 106 (1.18 g, 1.6 mmol), 1,3-dimethylbarbituric acid (0.6 g, 3.8 mmol) and Pd(PPh 3
)
4 (90 mg) in EtOAc/CH 2 Cl2 (60:40, 15 mL) yielded after 3 35 h and after FC (CH2Ci/EtOH 100:0 to 80:20) the amino acid 107 (0.86 g, 87%).
WO 2011/015241 PCT/EP2009/060168 220 Data of 107: C 3 1
H
4 ,NOsSi (628.8) . LC-MS: (method 6): Rt = 1.08 (88), 629 ([M+H]+). 5 Synthesis of the protected macrolactam Ex.164 According to procedure F.1.2, amino acid 107 (310 mg, 0.49 mmol) in dry DMF (5 mL) was treated with FDPP (379 mg, 0.99 mmol) in dry DMF (500 mL) to afford after FC (hexane/EtOAc/MeOH 50:50:0 to 0:95:5) the macrolactam Ex.164 (131 mg, 43%). 10 Data of Ex.164: C 3 1
H
4 2
N
4 0 7 Si (610.8) . LC-MS: (method 7) : RL = 1.34 (98), 611 ( [M+H]) . 'H-NMR (DMSO-d 6 ): 7.42-7.27 (m, 8 H), 6.98 (dd, J = 1.4, 8.2, 1 H), 6.91 (d, J = 7.5, 1 H), 6.84 (s, 1 H), 4.98 (s, 2 H), 4.50 (d, J = 11.9, 1 H), 4.35-4.15 (m, 3 H), 4.06-3.96 (m, 4 H), 3.21 (m, 1 H), 3.10-2.95 (m, 2 H), 2.87 15 (s, 3 H), 2.30-1.80 (m, 4 H), 0.91 (t, J = 8.3, 2 H), 0.00 (s, 9 H). Synthesis of the amine Ex.165 20 At 0 0 C, a solution of TBAF in THF (1 M, 3.9 mL, 3.9 mmol) was added to a solution of Ex.164 (1.2 g, 1.96 mmol) in THF (42 mL). The solution was allowed to stir at 0 C to room temperature for 15 h, followed by the addition of more TBAF in THF (1 M, 1.18 mL, 1.18 mmol). Stirring was continued for 2 h. 25 The solution was distributed between CH 2 Cl2 and H 2 0. The aqueous phase was repeatedly extracted with CH2Cl. The combined organic phase was dried (Na 2
SO
4 ), filtered and concentrated. FC
(CH
0 Cl,/MeOH 100:0 to 90:10) afforded Ex.165 (0.76 g, 83%) Data of Ex.165:C 2 H30140N (466.52) . LC-MS: (method 4a) : Rt = 1.49 30 (99), 467 ([M+H]+). Core 11: Synthesis of Ex.181 and Ex.182 (Scheme 15) 35 Synthesis of the Mitsunobu product 108 WO 2011/015241 PCT/EP2009/060168 221 Following procedure B.1.2, the reaction of phenol 65 (10.7 g, 24 mmol), alcohol 16 (10.0 g, 29 mmol), and CMBP (12.0 g, 49 mmol) in dry toluene (362 mL) afforded after FC (hexane/EtOAc 50:50 to 70:30) the protected amino acid 108 (14.55 g, 78%). 5 Synthesis of the amino acid 109 Following procedure B.2, the reaction of 108 (14.50 g, 19 mmol), 1,3-dimethylbarbituric acid (7.0 g, 47.0 mmol) and 10 Pd(PPh 3
)
4 (0.1 g) in EtOAc/CH 2 Cl 2 (55:45, 203 mL) yielded after 3 h and after FC (CH 2 Cl 2 /MeOH 99:1 to 90:10) the amino acid 109 (11.26 g, 92%). Data of 109: C32H 4 6 N0,sSi (642.8) . LC-MS: (method 6): Rt = 1.13 (94), 643 ([M+H]) 15 Synthesis of the protected macrolactam Ex.181 According to procedure F.1.1, the amino acid 109 (4.0 g, 6.2 mmol) in dry CH 2 Cl 2 (100 mL) was treated with T3P (50% in 20 EtOAc, 7.4 mL, 12.4 mmol) and i-Pr 2 NEt (4.3 mL, 24.8 mmol) in dry CH2C1 2 (560 mL) . Prior to aqueous workup, the CHICl 2 was replaced by EtOAc. FC (hexane/EtOAc 50:50 to 0:100) afforded the macrolactam Ex.181 (2.11 g, 54%). Data of Ex.181: C 3 2
H
4 4 1 4 0 7 Si (624.8) . LC-MS (method 7): Rt = 1.37 25 (99), 625 ([M+H]) . H-NMR (DMSO-ds) : 7.46 (d, J = 8.0, 1 H), 7.42 (d, J = 7.2, 1 H), 7.34-7.23 (m, 6 H), 7.06 (d, J = 8.2, 1 H), 6.82 (d, J = 7.4, 1 H), 6.78 (s, 1 H), 5.02-4.86 (m, 3 H), 4.13 (t, J = 8.5, 1 H), 4.06-3.67 (m, 7 H), 3.05 (hr. m, 1 H), 2.88 (br. m, 1 H), 2.88 (s, 3 H), 2.15 (m, 2 H), 1.51 (br. m, 2 30 H), 1.33 (br. m, 1 H), 1.12 (br. m, 1 H), 0.91 (t-like m, J ca. 8.4, 2 H), 0.00 (s, 9 H). Synthesis of the amine Ex.182 35 According to procedure 1.2, carbamate Ex.181 (844 mg, 1.3 mmol) in THF (34 mL) was treated with TBAF solution (4.1 mL) to WO 2011/015241 PCT/EP2009/060168 222 afford after FC (CH2Cl 2 /MeOH 90:10) the amine Ex.182 (620 mg, 95%) Data of Ex.182: C, 6
H
3 2N 4 0 5 (480.5) . LC-MS: (method 2): R- = 1.35 (99), 481 ([M+H]K) 5 Core 12: Linear synthesis of Ex.196 and Ex.197 (Scheme 16) 10 Synthesis of the Mitsunobu product 110 Following procedure B.1.1, the reaction of phenol 59 (5.22 g, 12.6 mmol), alcohol 16 (5.2 g, 15.2 mmol), PPh- (5.0 g, 19 mmol) in dry benzene (124 mL) and DEAD (40% in toluene, 7.0 mL, 15.2 mmol) in dry benzene (36 mL) afforded after FC 15 (hexane/EtOAc 60:40 to 40:60) the protected amino acid 110 (8.3 g, 88%, contaminated with some triphenylphosphine oxide; acceptable for the use in the next stop without further purification). 20 Synthesis of the amino acid 111 Following procedure B.2, the reaction of 110 (4.15 g, 5.62 mmol), 1,3-dimethylbarbituric acid (2.19 g, 14.0 mmol) and Pd(PPh3) 4 (0.71 g) in EtOAc/CH 2 Cl 1:1 (60 mL) yielded after 1 h 25 and after FC (CH2Cl2/EtOH 95:5 to 90:10 then CH 2 Cl 2 /MeOH 90:10 to 70:30) amino acid 111 (2.75 g, 80%). Data of 111: C3oH 4 2 N40 8 Si (614.8) . HPLC (10% CH 3 CN) : Rt = 3.82 (99). LC-MS (method 9a) : R = 1.81; 615 ([M+H]K) 30 Synthesis of the alloc protected amino acid 112 Following procedure C.1, the reaction of the amino acid 111 (1.5 g, 2.4 mmol), allyl choroformate (0.29 mL, 2.68 mmol) and Na2CO 7 (0.72 g, 6.83 mmol) in dioxane (40 mL) and H20 (40 mL) 35 gave acid 112 (1.7 g, 100%).
WO 2011/015241 PCT/EP2009/060168 223 Synthesis of the protected amino acid 113 Following procedure C.2, the acid 112 (1.7 g, 2.4 mmol) was reacted with sarcosine allylester p-toluenesufonate (46.p-TsOH, 5 0.88 g, 2.9 mmol), HOAt (0.5 g, 3.6 mmol), HATU (1.4 g, 3.6 mmol) and i-Pr 2 NEt (2.1 mL, 12 mmol) in DMF (25 mL) to afford the protected amino acid 113 (1.51 g, 75%). Data of 113: C 4
H--N
5
O
1 nSi (809. 9) . HPLC (40% CH 3 CN) : R, = 4 .43 (91). LC-MS (method 9c): Rt = 2.51, 810 ([M+H]K) 10 Deprotection to amino acid 114 Following procedure C.3, the reaction of the protected amino acid 113 (1.5 g, 1.85 mmol), 1,3-dimethylbarbituric acid (0.72 15 g, 4.6 mmol) and Pd(PPh 3
)
4 (0.23 g) in EtOAc/CHCl 2 (1:1, 25 mL) yielded amino acid 114 (1.05 g, 83%). Data of 114: C33H 47
N
5 OSi (685.8) . HPLC (10% CH3CN) : Rt = 3.85 (95). LC-MS (method 9c): Rt = 1.78, 686 ([M+H]+). 20 Synthesis of the protected macrolactam Ex.196 According to procedure F.1.2, amino acid 114 (1.0 g, 1.46 mmol) in dry DMF (20 mL) was treated with FDPP (1.12 g, 2.92 mmol) in dry DMF (130 mL) to yield after FC (EtOAc) the macrolactam 25 Ex.196 (0.61 g, 63%). Data of Ex.196: C 3 3
H
4 5
N
5 OsSi (667.8) . LC-MS (method la) : Rt = 2.66 (100), 668 ([M+H]K). LC-MS (method 9c): R- = 2.12, 668 ([M+H]+), 640. 'H-NMR (CDCl 3 ) : 7.34-7.26 (m, 6 H), 7.17 (d, J = 7.6, 1 H), 7.02 (s, 1 H), 6.91 (d, J = 9.5, 1 H), 5.49 (d, J = 30 9.5, 2 H), 5.10 (m, 1 H), 5.06 (s, 2 H), 4.39-4.13 (m, 5 H), 4.00-3.95 (m, 2 H), 3.65 (m, 1 H), 3.36 (br. s, 2 H), 3.14 (m, 2 H), 3.09 (s, 3 H), 2.74 (s, 3 H), 2.45 (m, 1 H), 2.08 (m, 1 H), 0.98 (m, 2 H), 0.00 (s, 9 H). 'H-NMR (DMSO-d 6 ): 7.98 (d, J = 9.9, 1 H), 7.52 (d, J = 7.9, 1 H), 7.36-7.27 (m, 6 H), 7.18 35 (s, 1 H), 7.06 (dd, J = 1.8, 8.1, 1 H), 6.83 (d, J = 7.5, 1 H), 5.12 (d, J = 12.5, 1 H), 5.04 (d, J = 12.5, 1 H), 4.87 (d, J = WO 2011/015241 PCT/EP2009/060168 224 8.8, 1 H), 4.25-3.89 (m, 8 H), 3.71-3.66 (m, 2 H), 3.20 (m, 1 H), 3.02 (m, 1 H), 2.97 (s, 3 H), 2.65 (s, 3 H), 2.20 (m, 1 H), 2.09 (m, 1 H), 0.92 (t, J = 8.2, 2 H), 0.00 (s, 9 H). 5 Synthesis of the amine Ex.197 According to procedure I.1, carbamate Ex.196 (120 mg, 0.18 mmol) in dioxane (3 mL) was treated with 4 M HCl-dioxane (3 mL) to afford Ex.197'HC1 (59 mg, 58%) . 10 Data of Ex.197-HC1: C? 7
H
33
N
5 06HCl (523.5, free base). HPLC (5% CH3CN) Rt = 3.05 (83). LC-MS (method 9c): Rt = 1.12, 524 ([M+H]) . 'H-NMR (DMSO-d 6 ): 8.53 (br. s, NH3+), 8.03 (d, J = 9.9, 1 H), 7.41-7.31 (m, 7 H), 7.15 (m, 1 H), 6.85 (d, J = 7.5, 1 H), 5.14 (d, J = 12.5, 1 H), 5.04 (d, J = 12.5, 1 H), 4.86 15 (dd, J ca. 2.2, 11.0, 1 H), 4.42-4.13 (m, 2 H), 4.05 (t, J 8.5, 1 H), 3.96 (d, J = 17.8, 1 H), 3.85-3.75 (m, 2 H), 3.65 (br. m, 1 H), ca. 3.3-3.1 (m, 3 H, partially superimposed by the H 2 0 signal), 2.97 (s, 3 H), 2.67 (s, 3 H), 2.42 (m, 1 H), 2.18 (br. q, J ca. 11.1, 1 H) 20 Core 12: Convergent synthesis of Ex.197 and Ex.198 (Scheme 17) 25 Synthesis of the Mitsunobu product 115 Following procedure E.1.1, phenol 59 (4.6 g, 11 mmol) was treated for 40 h with alcohol 81 (5.0 g, 13 mmol), DEAD (40% in toluene, 6.1 mL, 13 mmol) and PPh3 (4.4 g, 17 mmol) in dry 30 benzene (150 mL) . After 2h and after 18 h, more PPh] (1.82 g, 6.9 mmol), alcohol 81 (2.04 g, 5.5 mmol) in benzene (50 mL), and DEAD (40% in toluene, 2.55 mL, 5.6 mmol) in benzene (13 mL) were added. FC (hexane/EtOAc 50:50 to 90:10) afforded the protected amino acid 115.1 (2.5 g, 29%). 35 WO 2011/015241 PCT/EP2009/060168 225 Following procedure E.1.2, the reaction of phenol 59 (2.9 g, 7.0 mmol), alcohol 81, (5.7 g, 15 mmol) and CMBP (5.1 g, 21 mmol) in dry toluene (121 mL) afforded after FC (hexane/EtOAc 20:80 to 90:10) the protected amino acid 115.2 (2.92 g, 54%). 5 Synthesis of the amino acid 116 Following procedure E.2, the reaction of 115.1 (3.17 g, 4.14 mmol), 1,3-dimethylbarbituric acid (1.62 g, 10.3 mmol) and 10 Pd(PPh 3
)
4 (0.53 g) in EtOAc/CH2Cl, (1:1, 46 mL) yielded after 1 h and after FC (CH 2 Cl 2 /MeOH 90:10 to 70:30) the amino acid 116.1 (1.86 g, 70%). Data of 116.1: C3 2
H
4 3N O 0 (641.7) . HPLC (5% CH 3 CN) : Rt = 3.65 (100). LC-MS (method 9c): RL = 1.60, 642 ([M+H]). 15 Following procedure E.2, the reaction of 115.2 (2.9 g, 3.8 mmol), 1,3-dimethylbarbituric acid (1.5 g, 9.5 mmol) and Pd(PPh 3
)
4 (0.48 g) in EtOAc/CHCl 2 (1:1, 46 mL) yielded after 1 20 h and after FC (CH2Cl2/MeOH 90:10 to 70:30) the amino acid 116.2 (2.0 g, 83%). Data of 116.2: C 3 2H 4 3 N5Og (641.7) . HPLC (5% CH 3 CN) : Rt = 3.73 (98). LC-MS (method 9c) : Rt = 1.61, 642 ([M+H]) 25 Synthesis of the protected macrolactam Ex.198 According to procedure F.1.1, the amino acid 116.1 (1.0 g, 1.6 mmol) in dry CH 2 Cl2 (200 mL) was treated with T3P (50% in EtOAc, 1.8 mL, 3.1 mmol) and i-Pr 2 NEt (1.1 mL, 6.2 mmol) in dry 30 CH 2 Cl 2 (1400 mL) to afford after FC (EtOAc/MeOH 95:5 to 80:20) the macrolactam Ex.198 (containing 15% of the epimer Ex.231; 0.38 g, 39%). Data of Ex.198: C32H 4 eNtO (623.7) . LC-MS: (method 2): R- = 1.78 (84), 624 ([M+H]K); 1.82 (15). LC-MS (method 9c) : R = 1.87, 35 624 ([M+H]K).
WO 2011/015241 PCT/EP2009/060168 226 'H-NMR (CDCl): 7.42-7.25 (m, 7 H), 7.07 (s, 1 H), 7.00 (d, J = 8.2, 1 H), 5.59 (d, J = 9.5, 1 H), 5.38 (br. d, J ca 7.9, 1 H), 5.18 (dd, J = 2.5, 12.2, 1 H), 5.13 (s, 2 H), 4.43-4.01 (m, 5 H), 3.73 (m, 1 H), 3.47 (d, J = 17.7, 1 H), 3.33 (d, J = 17.7, 5 1 H), 3.20-3.11 (m, 2 H), 3.17 (s, 3 H), 2.81 (s, 3 H), 2.50 (m, 1 H), 2.15 (m, 1 H), 1.51 (s, Boo, major isomer), 1.45 (s, Boc, minor isomer); 'H-NMR (DMSO-d 6 ): 7.97 (d, J = 10.3, 1 H), 7.41-7.30 (m, 7 H), 7.18 (s, 1 H), 7.09 (d, J = 8.2, 1 H), 6.85 (J = 7.6, 1 H), 5.12 (d, J = 12.5, 1 H), 5.05 (d, J = 12.6, 1 10 H), 4.89 (J = 9.6, 1 H), 4.30-3.55 (m, 6 H), 3.40 (2 H, superimposed by H 2 0 signal), 3.25-3.00 (n, 2 H), 2.99 (s, 3 H), 2.65 (s, 3 H), 2.22 (m, 1 H), 2.05 (br. q, 1 H), 1.41, (s, 9 H). 15 According to procedure F.1.1, amino acid 116.2 (0.85 g, 1.3 mmol) in dry CH 2 C1 2 (170 mL) was treated with T3P (50% in EtOAc, 1.56 mL, 2.6 mmol) and i-Pr 2 NEt (0.91 mL, 5.3 mmol) in dry CH2Cl 0 (1190 mL) to afford after FC (EtOAc/MeOH 95:5 to 20 80:20) the macrolactam Ex.198 and its epimer Ex.231 (ca 1:1 mixture; 0.61 g, 73%). Data of the mixture Ex.198/Ex.231: C 32
H
41
N
5 O (623.7) . LC-MS: (method 2): Rt = 1.78 (44), 624 ([M+H]K) ; 1.82 (56), 624 ([M+H]) . 'H-NMR (CDCl3): complex spectrum, mixture of epimers, 25 7.41-7.20 (n, 6 H), 7.07-6.92 (n, 3 H) 5.8-4.8 (several m, 5 H), 4.3-3.0 (several m, 10 H), 3.16 (s, NCH 3 ), 2.81 (s, NCH 3 ), 2.58-2.45 (n, 1 H), 2.19-2.03 (n, 1 H), 1.51, 1.41 (2 s, 9 H) 30 Synthesis of the amine Ex.197 According to procedure J, carbamate Ex.198/Ex.231 (ca. 85:15, 749 mg, 1.2 mmol) in dioxane (7.5 mL) was treated with 4 M HCE dioxane (15 mL) to afford Ex.197'HCl/Ex.232'HCl (607 mg, 90%). Data of Ex.197'HCl/Ex.232'HCl: C 27 H33N 5 0 6 'HCl (523.5, free base). 35 LC-MS (method 2): Rt = 1.26 (75), 1.33 (14); 524 ( [M+H]).
WO 2011/015241 PCT/EP2009/060168 227 H-NMR (DMSO-d 6 ), major component Ex.197'HCl: spectrum identical with the one described above for compound Ex.197HCl (cf. Scheme 16). 5 According to procedure J, carbamate Ex.198/Ex.231 (ca. 1:1, 1.32 g, 2.12 mmol) in dioxane (13 mL) was treated with 4 M HCl dioxane (26 mL) to afford after separation of the isomers by preparative RP-HPLC (method 1) Ex.197'TFA (460 mg, 34%) and 10 Ex.232-TFA (470 mg, 35%). Data of Ex.197'TFA: C 27
H
33
N
5 O0'C2HF30 2 (523.5, free base) . LC-MS (method 2): RL = 1.25 (99), 524 ([M+H]+). LC-MS (method 7): R = 0.74 (97), 524 ([M+H]) . 'H-NMR (DMSO-ds): 8.34 (br. s, NH3), 8.07 (d, J = 9.9, 1 H), 7.43-7.33 (m, 6 H), 7.20 (s, 1 H), 7.10 15 (dd, J = 1.5, 8.2, 1 H), 6.87 (d, J = 7.4, 1 H), 5.17 (d, J = 12.5, 1 H), 5.05 (d, J = 12.5, 1 H), 4.87 (br. dd, 1 H), 4.27 4.16 (m, 2 H), 4.06 (t, J = 8.6, 1 H), 4.01-3.91 (m, 2 H), 3.82 (t-like dd, J ca. 8.1, 1 H), 3.70 (br. m, 1 H), 3.35-3.20 (m, 3 H), 2.98 (s, 3 H), 2.70 (s, 3 H), 2.49 (m, 1 H), 2.18 (br. q, J 20 ca 11.0, 1 H). Data of Ex.232'TFA: See below; Core 14. 25 Core 13: Synthesis of Ex.215 and Ex.216 (Scheme 18) Synthesis of the Mitsunobu product 117 Following procedure B.1.1, the reaction of phenol 59 (2.1 g, 5.1 mmol), alcohol 20 (2.1 g, 6.1 mmol), PPha (2.0 g, 7.6 mmol) 30 in dry benzene (50 mL) and DEAD (40% in toluene, 2.8 mL, 6.1 mmol) in dry benzene (14 mL) afforded, after further addition of PPh 3 (0.84 g, 3.2 mmol), alcohol 20 (0.88 g, 2.6 mmol) in benzene (21 mL) and DEAD (40% in toluene, 1.2 mL, 2.6 mmol) in benzene (6 mL) and after FC (hexane/EtOAc 50:50) the protected 35 amino acid 117 (3.8 g, 100%).
WO 2011/015241 PCT/EP2009/060168 228 Synthesis of the amino acid 118 Following procedure B.2, the reaction of 117 (7.63 g, 10.3 mmol), 1,3-dimethylbarbituric acid (4.03 g, 25.8 mmol) and 5 Pd(PPh3)4 (1.31 g) in EtOAc/CH 2 Cl? (1:1, 110 mL) yielded after 1 h and after FC (CH 2 Cl 2 /MeOH 95:5 to 70:30) the amino acid 118 (3.48 g, 60%). Data of 118: C 3 0H 4 2 N40 8 Si (614.8) . HPLC (10% CH 3 CN) RL = 3.88 (100). LC-MS (method 9a): Rt = 1.80, 615 ([M+H]*) 10 Synthesis of the alloc protected amino acid 119 Following procedure C.1, the reaction of the amino acid 118 (3.36 g, 5.5 mmol), allyl choroformate (0.64 mL, 6.0 mmol) and 15 Na 2
CO
3 (0.87 g, 8.2 mmol) in dioxane (51 mL) and H 2 0 (51 mL) gave the acid 119 (3.51 g, 92%). Synthesis of the protected amino acid 120 20 Following procedure C.2, acid 119 (3.47 g, 5.0 mmol) was reacted with sarcosine allvlester p-toluenesufonate (46.p-TsOH, 1.8 g, 6.0 mmol), HOAt (1.0 g, 7.4 mmol), HATU (2.8 g, 7.4 mmol) and i-Pr 2 NEt (4.2 mL, 25 mmol) in DMF (108 mL) to afford the protected amino acid 120 (3.52 g, 88%). 25 Data of 120: C 40
H,,N>O
1 ,Si (809.9). LC-MS: (method 4b) : R = 2.51 (95), 810 ([M+H]+) Deprotection to amino acid 121 30 Following procedure C.3, the reaction of the protected amino acid 120 (3.49 g, 4.31 mmol), 1,3-dimethylbarbituric acid (1.68 g, 10.8 mmol) and Pd(PPh 3
)
4 (0.55 g) in EtOAc/CH 2 Cl 0 (1:1; 50 mL) yielded the amino acid 121 (2.72 g,92%). Data of 121: C3 3
H
4 7
N
5
O
9 Si (685.8) . LC-MS: (method 4b): R- = 1.84 35 (94), 686 ([M+H]*) WO 2011/015241 PCT/EP2009/060168 229 Synthesis of the protected macrolactam Ex.215 According to procedure F.1.2, amino acid 121 (1.33 g, 1.94 mmol) in dry DMF (27 mL) was treated with FDPP (1.49 g, 3.88 5 mmol) in dry DMF (164 mL) to yield after FC (EtOAc/MeOH 95:5) macrolactam Ex.215 (0.89 g, 68%). Data of Ex.215: C33H 45 NOqSi (667.8). LC-MS: (method 1b): R = 2.60 (99), 668 ( [M+H]) . LC-MS: (method 9c): R- = 2.14, 668 ([M+H]) . 'H-NMR (DMSO-d 6 ): 7.94 (d, J = 9.8, 1 H), 7.39-7.27 10 (m, 7 H), 7.11 (s, 1 H), 6.97 (dd, J = 1.5, 8.2, 1 H), 6.82 (d, J = 7.5, 1 H), 5.05 (s, 2 H), 4.83 (br. d, 1 H), 4.25 (hr. m, 1 H), 4.17-3.96 (m, 5 H), 3.73 (br. q, J ca. 16.8, 2 H), 3.47 (m, 1 H), 3.33 (m, 1 H), 3.19 (m, 2 H), 2.96 (s, 3 H), 2.67 (s, 3 H), 2.20 (m, 1 H), 2.00 (m, 1 H), 0.91 (t, J = 8.4, 2 H), 0.00 15 (s, 9 H). Synthesis of the amine Ex.216 According to procedure I.1, carbamate Ex.215 (881 mg, 1.3 mmol) 20 in dioxane (16 mL) was treated with 4 M HCl-dioxane (16 mL) to afford Ex.216*HC1 (666 mg, 90%). Data of Ex.216-HC1: C2 7 H33-N5OHC1 (523.5, free base) . HPLC (5%
CH
3 CN) Rt = 3.11 (91). LC-MS (method 9c): Rt = 1.19, 524 ([M+H]) 25 Core 14: Synthesis of Ex.231 and Ex.232 (Scheme 19) 30 Synthesis of the Mitsunobu product 122 A mixture of phenol 61 (4.6 g, 11.2 mmol) and PPh. (5.27 g, 20.1 mmol) was dissolved in benzene. The solution was concentrated and the residue was dried i.v. for 20 min. A solution of the alcohol 81, (7.46 g, 20.1 mmol) in dry, 35 degassed benzene (120 mL) was added. The resulting mixture was cooled to 0 C. DEAD (40% in toluene, 11.5 mL, 25.1 mmol) WO 2011/015241 PCT/EP2009/060168 230 in benzene (10 mL) was slowly added. The solution was stirred at room temperature for 16 h. More PPh 3 (1.46 g, 5.6 mmol), alcohol 81 (1.04 g, 2.8 mmol) and at 0 0 C, a solution of DEAD (40% in toluene, 2.6 mL, 5.7 mmol) in benzene (2 mL) were added 5 and stirring at room temperature was continued for 7 h. More PPh 3 (1.46 g, 5.6 mmol), alcohol 81 (1.04 g, 2.8 mmol), and at 0 0 C, a solution of DEAD (40% in toluene, 2.6 mL, 5.7 mmol) in benzene (2 mL) were added. Stirring at room temperature was continued for 16 h. The mixture was concentrated. FC 10 (hexane/EtOAc 30:70 to 0:100) afforded 122 (12.8 g, contaminated with ca 40% triphenylphosphinoxide, yield ca 90%). The material was used for the next step without further purification) 15 Synthesis of the amino acid 123 Following procedure E.2, the reaction of the protected amino acid 122 (contaminated with ca 40% of triphenylphosphine oxide, 12.8 g, ca 10 mmol), 1,3-dimethylbarbituric acid (3.91 g, 25.1 20 mmol) and Pd(PPh 3
)
4 (1.27 g) in EtOAc/CH 2 Clz (1:1, 120 mL) yielded after 1 h and after FC (CH 2 Cl2/MeOH 100:0 to 70:30 then CHCl 3 /MeOH 70:30) the amino acid 123 (2.80 g, 44%). Data of 123: C 2H 4 N Og (641.7). LC-MS: (method 2): Rt = 1.56 (94), 642 ([M+H]+). 25 Synthesis of the protected macrolactam Ex.231 According to procedure F.1.2, amino acid 123 (3.29 g, 5.13 mmol) in dry DMF (150 mL) was added within 4 h at 60'C to FDPP 30 (3.94 g, 10.3 mmol) in dry DMF (4980 mL) to afford after 16 h at 60'C and after FC (EtOAc/MeOH 100:0 to 95:5) the macrolactam Ex.231 (contained ca 15% of its epimer Ex.198; 2.5 g, 78%). Data of Ex.231: C 3 2
H
4 Nt8 (623.7). LC-MS: (method 2): R- = 1.78 (12), 1.82 (83), 624 ([M+H]+). LC-MS: (method 7): R = 1.16 35 (18), 624 ([M+H]*); 1.18 (80), 624 ([M+H]K). H-NMR (CDCl3): complex spectrum, two epimers; 7.38-7.22 (m, 6 H), 7.06-6.90 WO 2011/015241 PCT/EP2009/060168 231 (m, 3 H), 5.80-4.80 (several m, 4 H), 5.08, 5.12 (2 s, 2 H), 4.43-2.80 (several br. m, 15 H), 2.51 (m, 1 H), 2.19-2.03 (m, 1 H), 1.50, 1.42 (2 s, 9 H). 5 Synthesis of the amine Ex.232 According to procedure J, carbamate Ex.231 (containing 15% of the epimer Ex.198; 1.42 g, 2.3 mmol) in dioxane (30 mL) was treated with 4 M HCl-dioxane (45 mL) to afford after 10 preparative RP-HPLC (method 1) Ex.232-TFA (1.10 g, 71%) and Ex.197"TFA (0.27 g, 17%). Data of Ex.232-TFA: C 27
H
3 3N 5 O(C2HF 3 0 2 (523.5, free base) . LC-MS (method 2): Rt = 1.32 (99), 524 ([M+H]K). 'H-NMR (DMSO-d,): complex spectrum, mixture of isomers; 8.40 (br. s), 8.20 (br. 15 s), 7.84 (d, J = 7.1), 7.50-6.80 (several m), 5.25-3.40 (several m, partially superimposed by the H20 signal), 3.30 2.80 (m), 3.04 (s, NCH3), 2.98 (s, NCH 3 ), 2.67 (s, NCH 3 ), 2.64 (s, NCH 3 ), 2.6-1.9 (several m). 20 Data of Ex.197-TFA: See above; Core 12. Core 15 and Core 16: 25 Synthesis of Ex.238 and Ex.239 (Scheme 20) Synthesis of the Mitsunobu product 124 Following procedure E.1.1, phenol 77 (1.63 g, 8.5 mmol), alcohol 85 (5.72 g, 12.8 mmol) and PPh 3 (4.02 g, 15.3 mmol) in 30 dry benzene (80 mL) were treated with DEAD (40% in toluene, 8.79 mL, 19.2 mmol) for 20 h. Purification by FC(hexane/EtOAc 20:80 to 100:0) then (hexane/EtOAc 50:50 to 20:80) afforded the protected amino acid 124 (1.96 g, 37%). 35 Synthesis of the macrocycle Ex.238 WO 2011/015241 PCT/EP2009/060168 232 Dichloro-[1,3-bis(mesityl)-2-imidazoldinylidene]-(3-phenyl-lH inden-1-ylidene) (tricyclohexylphosphine)ruthenium (II) (Umicore M2 catalyst; 88 mg) was added to a solution of 124 (1160 mg, 1.29 mmol) in dry, degassed CH 9 C1 2 (170 mL) . The 5 solution was stirred in a sealed tube at 40'C for 68 h, followed by 45 h at room temperature. During this period further equal portions of catalyst (in total 350 mg) were added after 20 h, 28 h, 44 h, and 52 h. The solution was concentrated. FC (hexane/EtOAc 70:30 to 0:100) gave Ex.238 (350 10 mg, 46%, mixture of two isomers, ratio > 9:1, acceptable for the use in the next step). An analytical sample (69 mg) was further purified by preparative RP-HPLC (method 2) to afford pure Ex.238 (major isomer; 45 mg). Data of Ex.238 (major isomer): C 3 2
H
40
N
4 0 7 (592.6). LC-MS: (method 15 4a): Rt = 2.23 (92), 593 ( [M+H]) . 'H-NMR (CDCl 3 ): 7.62-7.31 (m, 6 H), 7.07 (d, J = 7.6, 1 H), 6.99 (dd, J = 2.0, 7.9, 1 H), 6.85 (s, 1 H), 5.69-5.61 (n, 2 H), 5.48 (d, J = 8.2, 1 H), 5.21 (m, 1 H), 5.10 (s, 2 H), 4.76 (d, J = 10.1, 1 H), 4.54 (dt, J = 3.5, 7.9, 1 H), 4.41-4.25 (m, 2 H), 4.13 (d, J = 10.7, 1 H), 20 3.97 (m, 1 H), 3.62 (m, 2 H), 3.48 (m, 1 H), 3.10 (s, 3 H), 2.73 (n, 1 H), 2.60-2.45 (n, 2 H), 2.02 (n, 1 H), 1.46 (s, 9 H). 25 Synthesis of amine Ex.239 A solution of Ex.238 (430 mg, 0.73 mmol) in MeOH/THF 1:3, 36 mL) was hydrogenated for 3.5 h at room temperature and at normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H0; 215 mg) . The 30 mixture was filtered through a pad of celite. The filtrate was concentrated to give Ex.239 (355 mg, quantitative; used in the next step without further purification). An analytical sample (68 mg) was purified by preparative RP HPLC (method 2) to afford pure Ex.239 (37 mg). 35 Data of Ex.239: C2 4 H331 4 0 5 (460.6): LC-MS (method 7): Rt = 0.88 (97), 461 ([M+H]) . 'H-NMR (DMSO-d 6 ) : 7.36 (t, J = 7.8, 1 H), WO 2011/015241 PCT/EP2009/060168 233 7.25 (d, J = 6.1, 1 H), 7.03 (dd, J = 1.6, 8.2, 1 H), 6.88-6.65 (m, 2 H), 4.51 (d, J = 8.3, 1 H), 4.18 (t, J = 10.3, 2 H), 4.09 (br. s, 1 H), 3.96 (br. m, 2 H), 3.19-2.72 (m, 3 H), 2.92 (s, 3 H), 2.34 (m, 2 H), 2.05 (br. q, 1 H), 1.82 (m, 1 H), 1.60-0.85 5 (m, 5 H), 1.40 (s, 9 H), 0.82 (m, 1 H). Core 17: Synthesis of Ex.248 and Ex.249 (Scheme 21) 10 Synthesis of the Mitsunobu product 125 Following procedure E.1.1, phenol 68 (6.0 g, 14.6 mmol), alcohol 82 (9.75 g, 26.2 mmol), and PPh3 (6.88 g, 26.2 mmol) were treated in dry benzene (160 mL) with DEAD (40% in toluene, 15 15 mL, 32.8 mmol) for 40 h. After 18 h and after 25 h, more PPh 3 (1.27 g, 4.8 mmol) and DEAD (40% in toluene, 2.23 mL, 4.9 mmol) in benzene (2 mL) were added. FC (hexane/EtOAc 30:70 to 20:80) afforded the protected amino acid 125 (16.85 g, contaminated with ca 40% triphenylphosphinoxide, yield ca 85%). 20 The material was used for the next step without further purification) Synthesis of the amino acid 126 25 Following procedure E.2, the reaction of 125 (16.8 g, contaminated with ca 40% of triphenylphosphine oxide, ca. 12 mmol), 1,3-dimethylbarbituric acid (4.80 g, 30.8 mmol) and Pd(PPh 3
)
4 (1.56 g) in EtOAc/CHCl (1:1, 170 mL) yielded after 1 h and after FC (CH 2 Cl 2 /MeOH 0:100 to 70:30, then CHCl/MeOH 30 70:30) amino acid 126 (4.15 g, ca. 52%). Data of 126: C33H44N 4 Os (640.7). HPLC (10% CH<CN): R, = 3.67 (69). LC-MS (method 9c) : R = 1.75, 641 ([M+H]). 35 Synthesis of the protected macrolactam Ex.248 WO 2011/015241 PCT/EP2009/060168 234 According to procedure F.1.1, amino acid 126 (4.55 g, 7.1 mmol) in dry CH 2 Cl2 (120 mL) was added within 3 h to T3P (50% in EtOAc, 8.37 ml, 14.2 mmol) and i-Pr 2 NEt (4.83 ml, 28.4 mmol) in dry CH2Cl 0 (6660 mL) . Prior to aqueous workup, CH 2 C1 2 was 5 replaced with EtOAc. FC (CH2Cl,/MeOH 100:0 to 95:5) yielded the macrolactam Ex.248 (2.38 g, 54%). Data of Ex.248: C33H 4 2
N
4 09 (622.7) . LC-MS: (method 2): Re = 1.83 (100), 623 ( [M+H]) . LC-MS: (method 9c) : Rt = 1.97, 623 ([M+H]). 'H-NMR (DMSO-d 6 ): 7.45-7.34 (m, 5 H), 7.15-6.78 (m, 5 10 H), 5.25 (s, 2 H), 5.08 (d, J = 12.8, 1 H), 4.62 (d, J = 13.5, 2 H), 4.29 (m, 1 H), 4.09 (d, J = 7.3, 1 H), 3.89 (d, J = 12.4, 1 H), 3.54 (br. t, 1 H), 3.27 (m, 1 H), 3.07 (s, 3 H), 2.80 (m, 1 H), 2.71 (s, 3 H), 2.28-2.06 (m, 4 H), 1.94 (m, 1 H), 1.71 (m, 1 H), 1.39 (s, 9 H). 15 Synthesis of the acid Ex.249: According to procedure H, the ester Ex.248 (2.16 g, 3.5 mmol) was hydrogenated in MeOH (130 mL)/THF (40 mL) in the presence 20 of the catalyst (1.09 g) for 2.5 h to afford the acid Ex.249 (1.83 g, 99%). Data of Ex.249: C 2 6H 3
,N
4 09 (532.6). LC-MS: (method 2): R- = 1.42 (95), 533 ([M+H]) 25 Core 18: Synthesis of Ex.272, Ex.273, and Ex.274 (Scheme 22) Synthesis of the Mitsunobu product 127 30 Following procedure E.1.1, the reaction of phenol 71 (6.47 g, 15,7 mmol), the alcohol 81 (10.5 g, 28.2 mmol), DEAD (40% in toluene, 26 mL, 56.3 mmol), and PPh 3 (14.8 g, 56.3 mmol) in dry benzene (380 mL) afforded after 2 h at room temperature and after aqueous workup (EtOAc, sat. aq. Na 2
CO
3 soln, sat. aq. 35 NaCl soln), drying (Na 2
SO
4 ), concentration of the organic layer WO 2011/015241 PCT/EP2009/060168 235 and FC (hexane/EtOAc 30:70, 0:100, then CHC12/MeOH 90:10) the protected amino acid 127 (12.0 g, 99%). 5 Synthesis of the amino acid 128 Following procedure E.2, the reaction of 127 (12.0 g, 16 mmol), 1,3-dimethylbarbituric acid (5.9 g, 38.0 mmol) and Pd(PPh 3
)
4 (0.9 g) in EtOAc/CH 2 Cl2 (55:45, 275 mL) yielded after 2 h and after FC (EtOAc, then CH 9 Cl 2 /MeOH 90:10 to 60:40) the amino 10 acid 128 (9.05 g, 90%). Data of 128: C 3 1
H
4 2
N
6 0 9 (642.7). LC-MS: (method 7): Rt = 0.90 (94), 643 ([M+H]+). 15 Synthesis of the protected macrolactam Ex.272 According to procedure F.1.1, the amino acid 128 (5.04 g, 7.8 mmol) in dry CH 2 Cl 2 (100 mL) was treated with T3P (50% in EtOAc, 9.2 mL, 16 mmol) and i-Pr 2 NEt (5.4 mL, 31 mmol) in dry
CH
2 Cl2 (700 mL) to afford after FC (CH2Cl,/MeOH 39:1 to 19:1) 20 the epimeric macrolactams Ex.272 (1.90 g, 38%). Data of Ex.272: C, 1
H
40
N
6 01 (624.7). LC-MS: (method 2): R- = 1.61 (99), 625 ([M+H]) . LC-MS: (method 7): RL = 1.01 (99), 625 ([M+H]) . 'H-NMR (DMSO-ds): 8.47 (d, J = 2.6, 1 H), 8.12 (s, 1 H), 7.95 (d, J = 9.6, 1 H), 7.61 (s, 1 H), 7.40-7.29 (m, 6 H), 25 5.10 (d, J = 12.6, 1 H), 5.04 (d, J = 12.6, 1 H), 4.98 (br. d, J = 10.7, 1 H), 4.16 (br. d, J = 11.8, 1 H), 4.10-3.90 (m, 4 H), 3.71 (br. t, J ca. 8.4, 1 H), 3.65-3.40 (m, 2 H), 3.23 (br. dd, J = 11.1, 15.2, 1 H), 3.04 (s, 3 H), 2.92 (t, J = 9.6, 1 H), 2.66 (s, 3 H), 2.12 (m, 1 H), 2.09 (br. q, 1 H), 1.42 (s, 9 30 H). Synthesis of the amine Ex.273 According to procedure J, carbamate Ex.272 (3.12 g, 5 mmol) in 35 dioxane (31 mL) was treated with 4 M HCl-dioxane (62 mL) to afford Ex.273.2HCl (2.9 g, 97%) WO 2011/015241 PCT/EP2009/060168 236 Data of Ex.273.2HC1: C 26
H
3 2N 6 0 6 .2HC1 (524.5, free base) . LC-MS (method 2): Rt = 1.31 (92), 525 ([M+H]K) 5 Synthesis of the amine Ex.274 According to procedure K, carbamate Ex.272 (200 mg, 0.32 mmol) was hydrogenated in MeOH (20 mL) in the presence of the catalyst (100 mg) to afford Ex.274 (154 mg, 97%). Data of Ex.274: C 23
H
34
N
6 0 6 . (490.5). LC-MS (method 2): R- = 1.26 10 (98), (491 ( [M+H]+). Core 19: Synthesis of Ex.297 and Ex.298 (Scheme 23) 15 Synthesis of the Mitsunobu product 129 Following procedure E.1.2, the reaction of phenol 75 (4.58 g, 9.9 mmol), alcohol 81 (5.5 g, 15 mmol), and CMBP (4.8 g, 20 mmol) in dry toluene (24 mL) afforded after FC (hexane/EtOAc 20 1:3) the protected amino acid 129 (5.54 g, 68%). Synthesis of the amino acid 130 Following procedure E.2, the reaction of 129 (5.53 g, 6.8 25 mmol), 1,3-dimethylbarbituric acid (2.5 g, 16 mmol) and Pd(PPh3) 4 (0.39 g) in EtOAc/CHCl, 55:45 (118 mL) yielded after 2 h and after FC (CHCl 2 /MeOH 95:5 to 70:30) the amino acid 130 (1.45 g, 85%). Data of 130: Ca 0 HtNhOs (691.7). LC-MS (method 7): Rt = 1.09 30 (96), 692 ([M+H]+). Synthesis of the protected macrolactam Ex.297 According to procedure F.1.1, amino acid 130 (2.57 g, 3.7 mmol) 35 in dry CH 2 Cl (40 mL) was treated with T3P (50% in EtOAc, 4.4 mL, 7.4 mmol) and i-Pr 2 NEt (2.5 mL, 14.9 mmol) in dry CH 0 Cl2 WO 2011/015241 PCT/EP2009/060168 237 (330 mL) to give after FC (CH2Cl2/MeOH 99:1 to 90:10) the macrolactam Ex.297 (2.5 g, contaminated with ca 20% i-Pr2NEt; yield 80%). Data of Ex.297: C 3 6
H
4 3 N5O 8 (673.7). LC-MS: (method 7): R_ = 1.18 5 (93), 674 ([M+H]). Aqueous workup (EtOAc, 1 M aq. NaH 2 POW soln) of ananalytical sample (100 mg) afforded pure Ex.297 (81 mg). LC-MS: (method 2): R7 = 2.20 (93), 674 ([M+H]'). 'H-NMR (DMSO d):complex spectrum, several isomers, 8.51 (d, J = 8.5, 0.2 10 H), 8.47 (d, J = 8.7, 0.1 H), 8.40 (d, J = 8.5, 0.55 H), 8.32 (d, J = 8.5, 0.15 H), 7.68-7.10 (several m, 10 H), 5.96 (br. s, 0.3 H), 5.90 (br. s, 0.3 H), 5.4-5.0 (m, 2.4 H), 4.8-3.8 (several m, 8 H), 3.3-2.5 (several m and s, 8 H), 2.5-1.6 (several m, 4 H), 1.42, 1.41, 1.36, 1.26 (4 s, Boo). 15 Synthesis of the acid Ex.298: According to procedure H, the ester Ex.297 (2.0 g, contaminated with ca 20% i-Pr2NEt 2.4 mmol) was hydrogenated in MeOH (200 20 mL) in the presence of the catalyst (1 g) for 3 h. The crude product was suspended in diethyl ether (20 mL) stirred for 20 min, filtered, washed (diethyl ether) and dried to afford Ex.298 (1.63 g, contaminated with 15% i-Pr 2 NEt, quantitative yield). 25 Aqueous workup (CH2Cl2, 1 M aq. NaH 0
PO
4 soln) of an analytical sample (200 mg) afforded pure Ex.298 (135 mg). Data of Ex.298: C 2 3H.
3 NaOs (583.6). LC-MS: (method 4a): Rt = 1.78 (86), 584 ([M+H]). 30 Core 20: Synthesis of Ex.311 (Scheme 24) Synthesis of the Mitsunobu product 131 35 A solution of phenol 72 (200 mg, 0.34 mmol), alcohol 16 (178 mg, 0.52 mmol) and PPh 3 (180 mg, 0.69 mmol) in benzene (5 mL) WO 2011/015241 PCT/EP2009/060168 238 was degassed. At 0 0 C, DEAD (40% in toluene, 0.32 mL, 0.69 mmol) was added. The mixture was stirred at room temperature for 15 h. More of alcohol 16 (178 mg, 0.52 mmol) and PPh 3 (180 mg, 0.69 mmol) were added. DEAD (40% in toluene, 0.32 mL, 0.69 5 mmol) was added at 0 0 C. The mixture was stirred for 20 h and concentrated. FC (CH 2 Cl 2 /EtOAc 100:0 to 80:20) afforded 131 (containing ca. 20% of diethyl hydrazine-1,2-dicarboxylate; used without any further purification). 10 Synthesis of the amino acid 132 Following procedure B.2, the reaction of 131 (250 mg, ca. 80%, 0.22 mmol), 1.3-dimethylbarbituric acid (107 mg, 0.69 mmol) and Pd(PPh) 4 (16 mg) in EtOAc/CH 2 Cl 2 (55:45, 4.8 mL) yielded after 15 3 h and after FC (EtOAc/MeOH 100:0 to 90:10, then CH 2 Cl 2 /MeOH 90:10 to 80:20) 132 (177 mg, yield over the two steps: 73%). Data of 132: C39H 57
N
5 0 10 Si (784.0) : LC-MS: (method 7): R, = 1.31, 784.2 ([M+H]K). 20 Synthesis of the alloc protected amino acid 133 Following procedure C.1, the reaction of 132 (150 mg, 0.19 mmol), allyl chloroformate (23 JIL, 0.21 mmol) and Na2CO 3 (61 mg, 0.57 mmol) in dioxane (1.5 mL) and H2O (1.5 mL) gave, after 25 2 h at 0 0 C, acid 133 (154 mg, 92%). Synthesis of the protected amino acid 134 Following procedure C.2, acid 133 (140 mg, 0.16 mmol) was 30 reacted with sarcosine allylester p-toluenesulfonate (46'pTsOH, 58 mg, 0.194 mmol), HOAt (33 mg, 0.24 mmol), HATU (92 mg, 0.24 mmol) and i-Pr 2 NEt (0.138 mL, 0.81 mmol) in DMF (2.4 mL) to afford the protected amino acid 134 (106 mg, 67%). Data of 134: C 4 qHm 0N 6 1] 3 Si (979.2) . LC-MS: (method 7): Rt = 1.68, 35 979.3 ([M+H]).
WO 2011/015241 PCT/EP2009/060168 239 Synthesis of amino acid 135 Following procedure C.3, the reaction of the protected amino 5 acid 134 (100 mg, 0.10 mmol), 1.3-dimethylbarbituric acid (38 mg, 0.25 mmol) and Pd(PPh 3
)
4 (6 mg) in EtOAc/CH 2 Cl 2 (45:55, 1.9 mL) yielded after 16 h and after FC (EtOAc, then CH2Cl 2 /MeOH 90:10) 135 (70 mg, 80%). Data of 135: C 42 Hs 2
N
6 OnSi (855.1) . LC-MS: (method 7): Rt = 1.30, 10 855.5 ([M+H]). Synthesis of the protected macrolactam Ex.311 According to procedure F.1.1, a solution of the amino acid 135 15 (60 mg, 0.07 mmol) in dry CH2Cl 2 (2 mL), was added within 2 h to T3P (50% in EtOAc; 84 pL, 0.14 mmol) and i-Pr2NEt (48 gL, 0.28 mmol) in CH2Clz (5 mL). Then sat. aq. NaHCO 3 solution was added and the mixture was extracted with CH 0 C1 2 . The organic phase was dried (Na 2 SO), filtered and concentrated. FC (EtOAc) 20 afforded Ex.311 (26 mg, 44%). Data of Ex.311: (C 4 2 HCoNcO 1 0Si (837.0) . LC-MS: (method 7): R= 1.51 (90), 837.4 ([M+H]K). 'H-NMR (CDCl 3 ): 7.26 (s, 5 H), 7.09 (t, J = 8.4, 1 H), 6.78 (d-like m, 1 H), 6.61 (d, J = 7.4, 1 H), 5.50-4.90 (several br. m, 5 H), 4.90-3.80 (several br. m, 8 25 H), 3.69 (br. t, J ca. 8.5, 1 H), 3.6-2.3 (several br. m, 14 H), 2.12 (m, 1 H), 1.61 (m, 1 H), 1.38 (s, 9 H), 1.24 (s, 2 H), 0.93 (br. t, J ca. 8.0, 2 H), 0.00, -0.03 (2 s, 9 H). 30 Core 21: Synthesis of Ex.312 and Ex.313 (Scheme 25) Synthesis of the Mitsunobu product 136 Alcohol 82 (217 mg, 0.58 mmol) and CMBP (212 mg, 0.88 mmol) 35 were dissolved in dry degassed toluene (7 mL) and heated at WO 2011/015241 PCT/EP2009/060168 240 100'C for 30 min. A solution of 80 (250 mg, 0.58 mmol) in toluene (2 mL) was added dropwise. Stirring at 100 C was continued for 1 h. The volatiles were evaporated. FC (hexane/EtOAc 2:1 to 1:1) yielded 136 (290 mg, 63%). 5 Synthesis of aminoacid 137 Following procedure E.2 the reaction of 136 (250 mg, 0.32 mmol), 1,3-dimethylbarbituric acid (120 mg, 0.77 mmol) and 10 Pd(PPh 3
)
4 (18 mg) in EtOAc/CH 2 Cl 2 (45:55, 5.5 mL) yielded after 0.5 h and after FC (CH 2 Cl 2 /MeOH 95:5 to 70:30) the aminoacid 137 (164 mg, 78%). Data of 137: C33H 4 4 N0,sS (656.8) . LC-MS (method 7): Rt = 1.15 (95), 657 ([M+H]) 15 Synthesis of the protected macrolactam Ex.312 According to procedure F.1.1, a solution of the amino acid 137 (100 mg, 0.15 mmol) in dry CH 2 Cl 1 2 (2 mL) was added over 2 h to 20 T3P (50% in EtOAc, 0.18 mL, 0.31 mmol) and i-Pr 2 NEt (0.1 mL, 0.61 mmol) in dry CH 2 Cl 2 (13 mL) . Stirring at room temperature was continued for 1 h, followed by aqueous workup (EtOAc, sat. aq. NaHCO soln, Na2SO 4 ) and FC (EtOAc) to afford Ex.312 (56 mg, 57%). 25 Data of Ex.312: C 3 3H 4 2N40S (638.7). LC-MS (method 7): R- = 1.33 (95), 639 ([M+H]+). 'H-NMR (CDCl 3 ) : 7.37-7.23 (m, 8 H), 6.92 (br. s, 1 H), 5.25 (m, 2 H), 5.17 (s, 1 H), 4.88 (d, J = 16.2, 1 H), 4.62 (br. m, 1 H), 4.46 (br. t-like m, 1 H), 4.31 (br. m, 1 H), 4.17 (dd, J = 4.1, 14.2, 1 H), 3.72 (dd, J = 4.8, 10.7, 1 30 H), 3.50 (m, 1 H), 3.30-2.80 (several m, 2 H), 3.14 (s, 3 H), 3.01 (s, 3 H), 2.60-1.90 (several m, 6 H), 1.46 (s, 9 H). Synthesis of sulfon Ex.313 WO 2011/015241 PCT/EP2009/060168 241 m-CPBA (70% w/w; 10 mg, 41 mol) was added at 0 0 C to a solution of Ex.312 (20 mg, 31 jmol) in CH 2 C1 2 (0.5 mL). The mixture was stirred for 15 min followed by the addition of m-CPBA (9 mg, 37 pmol). The mixture was allowed to warm to room temperature over 5 1 h, diluted with CH>Cl and washed with aq. NazS 2 O3 soln and with aq. NaHCO 3 soln. The organic phase was dried (Na 2
SO
4 ), filtered and concentrated. FC (EtOAc/MeOH 100:0 to 90:10) afforded Ex.313 (8 mg, 38%). Data of Ex.313: C 3 3
H
4 2N 4 0 3 S (670.7). LC-MS (method 6): R- = 1.24 10 (95), 671 ([M+H]) . 'H-NMR (CDCl 3 ): 7.89 (td, J = 1.7, 7.3, 1 H), 7.71 (s, 1 H), 7.43-7.28 (m, 7 H), 5.17 (d, J = 12.0, 1 H), 5.10 (d, J = 12.0, 1 H), 5.01 (dd, J = 5.9, 9.1, 1 H), 4.96 4.85 (m, 2 H), 4.71 (d, J = 15.4, 1 H), 4.57 (br. m, 1 H), 4.33 (br. m, 2 H), 3.85 (dd, J = 7.8, 12.3, 1 H), 3.25 (s, 3 H), 15 3.20 (m, 1 H), 3.10 (m, 1 H), 2,97 (s, 3 H), 2.73-2.54 (m, 2 H), 2.45-2.23 (m, 2 H), 2.17 (m, 1 H), 1.99 (m, 1 H), 1.46 (s, 9 H). 20 Synthesis of final products Advanced macrocyclic intermediates and final products depicted in Tables 21a-36a (Scheme 26) and were prepared starting from 25 the suitable precursor macrocyclic acid or macrocyclic amine applying the general procedures (H-N) described above. Deviations from general procedures are indicated in Tables 21a 36a. Analytical data of these intermediates and final products are 30 depicted in Tables 21b-36b. IUPAC names of all examples are listed in Tables 20, 21c-36c, and 37. 35 Detailed description of selected examples: WO 2011/015241 PCT/EP2009/060168 242 Core 03: Synthesis of selected advanced intermediates and final products (Scheme 27) 5 Synthesis of amide Ex.27 A mixture of Ex.4 (432 mg, 0.79 mmol), HATU (597 mg, 1.57 mmol) and HOAt (214 mg, 1.57 mmol) was dissolved in DMF (6 mL). N,N dimethylethylenediamine (173 !IL, 1.57 mmol) and i-Pr 2 NEt (537 10 pL, 3.14 mmol) were added. The solution was stirred at room temperature for 15 h and concentrated. The residue was dissolved in CHCl 3 and washed with sat. aq. NaHCO 3 solution and with H20. The organic phase was dried (Na 2
SO
4 ), filtered and concentrated. FC (CH 2 Cl 2 /MeOH/conc. aq. NH 3 soln 100:0:0 to 15 90:10:0.5) afforded Ex.27 (405 mg, 83%). Data of Ex.27: Cf. Table 21b Synthesis of amine Ex.28 20 A solution of Ex.27 (400 mg, 0.64 mmol) in dioxane (4 mL) was treated at room temperature with 4 M HCl-dioxane (8 mL) for 2 h. The volatiles were evaporated. The residue was dissolved in
CH
2 Cl2/MeOH, concentrated and dried i.v. to afford Ex.28'HCl (343 mg, 90%). 25 Data of Ex.28: Cf. Table 21b Synthesis of amide Ex.11 A mixture of Ex.28'HCl (75 mg, 0.126 mmol), 'H-indole-3 -acetic 30 acid (44 mg, 0.253 mmol), HATU (96 mg, 0.253 mmol) and HOAt (34 mg, 0.253 mmol) was dissolved in DMF (2 mL). i-Pr 2 NEt (87 pL, 0.505 mmol) was added. The solution was stirred at room temperature for 15 h and concentrated. The residue was dissolved in CHCl 3 and washed with sat. aq. NaHCO 3 solution and 35 with H20. The organic phase was dried (NaS0 4 ), filtered and WO 2011/015241 PCT/EP2009/060168 243 concentrated. FC (CH 2 Cl,/MeOH/conc. aq. NH 3 soln 100:0:0 to 90:10:1) afforded Ex.11 (50 mg, 58%). Data of Ex.11: Cf. Table 21b 'H-NMR (DMSO-d): 10.81 (s, 1 H), 8.26 (d, J = 7.4, 1 H), 7.62 5 (t, J = 5.5, 1 H), 7.46 (d, J = 7.9, 1 H), 7.37-7.15 (m, 4 H), 7.09 (d, J = 2.2, 1 H), 7.04 (t, J = 7.5, 1 H), 6.92 (t, J ca. 7.4, 1 H), 5.08 (d, J ca. 12.5, 1 H), 4.74 (d, J = 8.9, 1 H), 4.37 (d, J = 11.0, 1 H), 4.25 (d, J = 17.7, 1 H), 4.22-4.13 (m, 2 H), 3.97 (d, J = 17.6, 1 H), 3.78 (t, J = 8.3, 1 H), 3.41 (s, 10 2 H), 3.24 (m, 1 H), 3.15 (m, 1 H), 2.98 (t, J = 9.2, 1 H), 2.88 (s, 3 H), 2.53 (s, 3 H), 2.41- 2.27 (m, 4 H), 2.17 (s, 6 H), 2.04 (m, 1 H), 1.83 (t-like m, 2 H), 1.69 (q-like m, 1 H). 15 Synthesis of amide Ex.49 A mixture of Ex.28'HC1 (60 mg, 0.101 mmol), 1-naphthylacetic acid (23 mg, 0.121 mmol), and HOBt.H2O (19 mg, 0.121 mmol) was dissolved in CH 2 C1 2 (1 mL). N-Cyclohexyl-carbodiimide-N' methylpolystyrene (1.9 mmol/g; 80 mg, 0.152 mmol) and i-PrNEt 20 (52 gL, 0.303 mmol) were added. The mixture was stirred for 15 h at room temperature. (Polystyrylmethyl)-trimethylammonium bicarbonate (3.5 mmol/g; 87 mg, 0.303 mmol) was added and stirring was continued for 1 h. The mixture was diluted with
CH
2 Cl2/MeOH 9:1 (2 mL) and filtered. The polymer was washed 25 with twice with CH2Cl 2 /MeOH 8:2 (5 mL). The combined filtrate and washings were concentrated. Purification of the crude product by FC (CH 2 Cl 2 /MeOH/conc. aq. NH 3 soln. 100:0:0 to 90:10:1) afforded Ex.49 (58 mg, 83%). Data of Ex.49: Cf. Table 21b 30 'H-NMR (DMSO-d) : 8.45 (d, J = 7.3, 1 H), 8.00-7.87 (m, 2 H), 7.79 (d, J = 8.0, 1 H), 7.62 (t, J = 5.5, 1 H), 7.53-7.25 (m, 6 H), 7.19 (dd, J = 3.0, 8.4, 1 H), 5.10 (d, J = 12.3, 1 H), 4.75 (d, J = 8.9, 1 H), 4.39 (d, J = 10.8, 1 H), 4.27 (d, J = 17.8, 1 H), 4.28-4.08 (m, 2 H), 3.95 (d, J = 17.9, 1 H), 3.83 (m, 1 35 H), 3.81 (s, 2 H), 3.24 (m, 1 H), 3.16 (m, 1 H), 3.03 (t, J = WO 2011/015241 PCT/EP2009/060168 244 9.2, 1 H), 2.87 (s, 3 H), 2.54 (s, 3 H), 2.42-2.27 (m, 4 H), 2.16 (s, 6 H), 2.02 (m, 1 H), 1.84 (t-like m, 2 H), 1.71 (q, J ca. 9.4, 1 H). 5 Synthesis of amide Ex.30 A mixture of Ex.4 (400 mg, 0.73 mmol), HATU (552 mg, 1.45 mmol), HOAt (198 mg, 1.45 mmol) and tryptamine (233 mg, 1.45 mmol) was dissolved in DMF (6 mL). i-Pr 2 NEt (497 p.L, 2.91 mmol) 10 was added. The solution was stirred at room temperature for 15 h followed by aqueous workup (CHC1 3 , sat. aq. NaHCO 3 soln, H 2 0) The organic phase was dried (Na 2
SO
1 ), filtered and concentrated. FC (CH2Cl 2 /MeOH 100:0 to 95:5) afforded Ex.30 (410 mg, 81%). 15 Data of Ex.30: Cf. Table 21b 'H-NMR (DMSO-d): 10.80 (s, 1 H), 7.91 (t, J = 5.6, 1 H), 7.56 (d, J = 7.7, 1 H), 7.32 (d, J = 8.0, 1 H), 7.27-7.12 (m, 5 H), 7.06 (t, J = 7.5, 1 H), 6.97 (t, J = 7.4, 1 H), 5.08 (d, J =12.4, 1 H), 4.75 (d, J = 9.3, 1 H), 4.34 (d, J = 10.9, 1 H), 20 4.24 (d, J = 17.8, 1 H), 4.10 (t-like m, 1 H), 3.97 (d, J = 17.7, 1 H), 3.86 (m, 1 H), 3.77 (m, 1 H), 3.42-3.30 (m, 2 H), 2.96-2.83 (m, 3 H), 2.89 (s, 3 H), 2.50 (s, 3 H, superimposed by DMSO-d signal), 2.27 (m, 2 H), 2.08 (m, 1 H), 1.84 (t-like m, 2 H), 1.65 (q, J = 10.8, 1 H), 1.34 (s, 9 H). 25 Synthesis of amine Ex.55 A solution of Ex.30 (380 mg, 0.55 mmol) in dioxane (4 mL) was treated at room temperature with 4 M HC1-dioxane (8 mL) for 4 30 h. The volatiles were evaporated. The residue was dissolved in dioxane (4 mL) and treated again for 2 h with 4 M HC1-dioxane (8 mL). The volatiles were evaporated. The residue was washed with diethyl ether and purified by FC (CH2Cl2/MeOH/conc. aq. NH, soln 90:10:0 to 90:10:1) to afford Ex.55 (136 mg, 42%). 35 Data of Ex.55: Cf. Table 21b WO 2011/015241 PCT/EP2009/060168 245 Synthesis of amide Ex.12 A mixture of Ex.55 (68 mg, 0.092 mmol), 1H-indole-3-acetic acid 5 (32 mg, 0.184 mmol), HATU (70 mg, 0.184 mmol) and HOAt (25 mg, 0.184 mmol) was dissolved in DMF (2 mL). i-Pr 2 NEt (63 gL, 0.367 mmol) was added. The solution was stirred at room temperature for 15 h and concentrated. The residue was dissolved in CHCl 3 and washed with sat. aq. NaHCO 3 solution and with H 2 0. The 10 organic phase was dried (Na2SO 4 ), filtered and concentrated. Purification by prep. HPLC, method 1, afforded Ex.12 (38 mg, 55%). Data of Ex.12: Cf. Table 21b 'H-NMR (DMSO-d 6 ): 10.81 (s, 2 H), 8.26 (d, J = 7.2, 1 H), 7.93 15 (t, J = 5.7, 1 H), 7.57 (d, J = 7.8, 1 H), 7.46 (d, J = 7.7, 1 H), 7.38-6.90 (m, 11 H); 5.10 (d, J = 12.1, 1 H), 4.76 (d, J = 9.3, 1 H), 4.38 (d, J = 10.8, 1 H), 4.26 (d, J = 17.8, 1 H), 4.23-4.11 (m, 2 H), 3.96 (d, J = 18.0, 1 H), 3.78 (t, J = 8.3, 1 H), 3.7-3.25 (m, 3 H), 3.60 (s, 2 H), 3.01 -2.81 (m, 2 H), 20 2.88 (s, 3 H), ca. 2.5 (s, 3 H, superimposed by DMSO-d signal), 2.33 (m, 2 H), 2.06 (m, 1 H), 1.85 (t-like m, 2 H), 1.63 (q, J ca. 10.7, 1 H). 25 Synthesis of amide Ex.16 A mixture of Ex.55 (68 mg, 0.092 mmol), N,N-dimethyl glycine (19 mg, 0.184 mmol), HATU (70 mg, 0.184 mmol) and HOAt (25 mg, 0.184 mmol) was dissolved in DMF (2 mL) . i-PrNEt (63 [L, 0.367 mmol) was added. The solution was stirred at room temperature 30 for 15 h and concentrated. The residue was dissolved in CHCl 3 and washed with sat. aq. NaHCO 3 solution and with HO. The organic phase was dried (Na 2
SO
4 ), filtered and concentrated. Purification by prep. HPLC, method 1, afforded Ex.16'TFA (40 mg, 55%). 35 Data of Ex.16"TFA: Cf. Table 21b WO 2011/015241 PCT/EP2009/060168 246 'H-NMR (DMSO-d) : 10.81 (s, 1 H), 9.66 (br. s, NH), 8.75 (d, J = 6.9, 1 H), 7.90 (t, J = 5.6, 1 H), 7.56 (d, J = 7.8, 1 H), 7.34-7.14 (m, 5 H), 7.06 (t, J ca. 7.5, 1 H), 6.97 (t, J = 7.4, 1 H), 5.08 (d, J = 12.3, 1 H), 4.78 (d, J = 9.2, 1 H), 4.39 (d, 5 J = 10.7, 1 H), 4.24 (d, J = 17.8, 1 H), 4.24-4.14 (m, 2 H), 4.00 (d, J = 17.8, 1 H), 3.96-3.75 (m, 3 H), 3.45-3.35 (m, 2 H), 3.0-2.67 (m, 3 H), 2.90 (s, 3 H), 2.75 (s, 6 H), 2.50 (s, 3 H, superimposed by DMSO-d signal), 2.5-2.27 (m, 2 H), 2.08 (m, 1 H), 1.85 (t-like m, 2 H), 1.64 (q, 3 = 10.8, 1 H). 10 Synthesis of amide Ex.53 Pyridine (2 mL) and acetic anhydride (0.14 mL, 1.48 mmol) were added to a solution of Ex.5-HCl (95 mg, 0.15 mmol) in dry CH 2 C12 15 (2 mL). The solution was stirred at room temperature for 20 h. The solution was diluted with EtOAc and washed with 1 M aq. HCl soln, sat. aq. NaCl soln, sat. aq. NaHCO 3 soln, and sat. aq. NaCl soln. The organic phase was dried (Na 2
SO
4 ), filtered and concentrated. FC of the crude product afforded Ex.53 (60 mg, 20 70%). Data of Ex.53: Cf. Table 21b Synthesis of acid Ex.54 25 A solution of Ex.53 (58 mg, 0.01 mmol) in MeOH (5 mL) was hydrogenated at room temperature and normal pressure for 2 h in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 50 mg) . The mixture was filtered through a pad of celite. The residue was washed (MeOH). The 30 combined filtrate and washings were concentrated and dried i.v. to yield Ex.54 (45 mg, 92%). Data of Ex.54: Cf. Table 21b 35 Synthesis of amide Ex.9 WO 2011/015241 PCT/EP2009/060168 247 A mixture of Ex.54 (45 mg, 0.091 mmol), HATU (52 mg, 0.137 mmol) HOAt (19 mg, 0.137 mmol) and tryptamine (22 mg, 0.137 mmol) was dissolved in DMF (1 mL). i-Pr 2 NEt (47 pL, 0.274 mmol) was added. The solution was stirred at room temperature for 20 5 h followed by aqueous workup (CHC1 3 , sat. aq. NaHCO 3 soln, H20) The organic phase was dried (Na2SO4), filtered and concentrated. FC (CH 2 Cl 2 /MeOH 100:0 to 86:14) afforded Ex.9 (36 mg, 62%). Data of Ex.9: Cf. Table 21b 10 'H-NMR (DMSO-d 6 ): 10.81 (s, 1 H), 8.06 (d, J = 7.0, 1 H), 7.93 (t, J = 5.6, 1 H), 7.56 (d, J = 7.8, 1 H), 7.34-7.14 (m, 5 H), 7.05 (t, J ca. 7.5, 1 H), 6.97 (t, J ca. 7.4, 1 H), 5.09 (d, J = 12.4, 1 H), 4.75 (d, J = 9.1, 1 H), 4.38 (d, J = 10.8, 1 H), 4.26 (d, J = 17.7, 1 H), 4.19-4.10 (m, 2 H), 3.97 (d, J = 17.9, 15 1 H), 3.78 (t, J = 8.3, 1 H), 3.43-3.30 (m, 2 H), 2.96-2.83 (m, 3 H), 2.89 (s, 3 H), 2.50 (s, 3 H, superimposed by DMSO-d signal), 2.40-2.27 (m, 2 H), 2.08 (m, 1 H), 1.85 (m, 2 H), 1.71 (s, 3 H), 1.62 (q, J ca. 10.6, 1 H). 20 Core 11 and Core 12: Synthesis of selected advanced intermediates and final products (Scheme 28) 25 Synthesis of amide Ex.184 A mixture of Ex 182 (500 mg, 1.04 mmol), 2-naphthylacetic acid (232 mg, 1.25 mmol), HATU (791 mg, 2.08 mmol) and HOAt (283 mg, 2.08 mmol) was dissolved in DMF (15 mL). i-PrNEt (712 gL, 4.16 30 mmol) was added. The solution was stirred at room temperature for 20 h and concentrated. The residue was dissolved in CHC1 3 and washed with sat. aq. NaHCO 3 solution and with H,0. The organic phase was dried (Na 2
SO
4 ), filtered and concentrated. FC (EtOAc, then CH 2 Cl 2 /MeOH 95:5) afforded Ex.184 (637 mg, 94%) 35 Data of Ex.184: Cf. Table 29b WO 2011/015241 PCT/EP2009/060168 248 'H-NMR (DMSO-d): 8.41 (d, J = 7.0, 1 H), 7.90-7.83 (m, 3 H), 7.77 (s, 1 H), 7.53-7.44 (m, 4 H), 7.32-7.22 (m, 6 H), 7.04 (d, J = 8.4, 1 H), 6.86 (d, J = 7.4, 1 H), 6.81 (s, 1 H), 5.02-4.90 (m, 3 H), 4.19 (t, J ca. 8.6, 1 H), 4.14-3.96 (m, 2 H), 3.83 5 (t-like m, 2 H), 3.63 (s, 2 H), ca. 3.3 (m, 1 H, superimposed by H 2 0 signal), 3.05 (m, 1 H), 2.95 (m, 1 H), 2.91 (s, 3 H), 2.27 (m, 1 H), 2.16 (br. q, J ca. 11.3, 1 H), 1.54 (m, 2 H), 1.31 (m, 1 H), 1.15 (m, 1 H). 10 Synthesis of aide Ex.200 A mixture of Ex.197TFA (60 mg, 0.094 mmol), 1H-indole-3-acetic acid (25 mg, 0.14 mmol), HATU (54 mg, 0.14 mmol) and HOAt (19 mg, 0.14 mmol) was dissolved in DMF (1.5 mL) . i-PrNEt (81 gL, 15 0.471 mmol) was added. The solution was stirred for 18 h at room temperature and concentrated. The residue was dissolved in CHC1 3 and washed (sat. aq. NaHCO 3 soln, H 2 0) . The organic phase was dried (Na 2
SO
4 ), filtered and concentrated, followed by FC (EtOAc, then CH 2 Cl 2 /MeOH 95:5) to afford Ex.200 (50 mg, 78%). 20 Data of Ex.200: Cf. Table 30b 'H-NMR (DMSO-d6): 10.86 (s, 1 H), 8.42 (d, J = 7.8, 1 H), 8.01 (d, J = 10.0, 1 H), 7.58 (d, J = 7.8, 1 H), 7.36-7.19 (m, 9 H), 7.07-7.02 (m, 2 H), 6.97 (t, J = 7.1, 1 H), 6.86 (d, J = 7.6, 1 H), 5.08 (s, 2 H), 4.88 (d, J = 8.7, 1 H), 4.30-4.10 (m, 2 H), 25 4.13 (d, J = 10.9, 1 H), 4.01 (t-like m, 1 H), 3.95 (d, J = 18.0, 1 H), 3.75-3.70 (m, 2 H), 3.56 (s, 2 H), 3.4-3.2 (m, 2 H, partially superimposed by H 2 0 signal), 3.04 (t, J = 9.9, 1 H), 2.98 (s, 3 H), 2.65 (s, 3 H), 2.27 (m, 1 H), 2.09 (q, J = 11.7, 1 H). 30 Synthesis of amine Ex.202 A solution of Ex.200 (320 mg, 0.47 mmol) in MeOH (28 mL) was hydrogenated at normal pressure and at room temperature for 4 h 35 in the presence of palladium hydroxide on activated charcoal WO 2011/015241 PCT/EP2009/060168 249 (moistened with 50% H 2 0; 158 mg) . The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrate and washings were concentrated and dried i.v. to yield Ex.202 (250 mg, 97%). 5 Data of Ex.202: Cf. Table 30b Synthesis of amide Ex.213 A solution of Ex.202 (60 mg, 0.11 mmol) in dry CH 2 C12 (1 mL) 10 was treated with pyridine (89 pL, 1.1 mmol). Decanoyl chloride (46 gL, 0.22 mmol) was slowly added at 0 0 C. The mixture was stirred at 0 0 C to room temperature for 18 h followed by the addition of MeOH (0.1 mL). Stirring was continued for 10 min. The volatiles were evaporated. The residue was three times 15 treated with toluene and evaporated. Purification by prep. HPLC, method 1 and subsequent FC (EtOAc/MeOH 90:10 to 80:20) afforded Ex.213 (27 mg, 35%). Data of Ex.213: Cf. Table 30b 'H-NMR (DMSO-d,): 10.86 (s, 1 H), 8.53 (d, J = 9.8, 1 H), 8.44 20 (d, J = 7.7, 1 H), 7.57 (d, J = 7.7, 1 H), 7.35-7.30 (m, 3 H), 7.27 (s, 1 H), 7.19-6.95 (m, 3 H), 6.84 (d, J = 7.5, 1 H), 4.86 (dd, J = 2.4, 11.2, 1 H), 4.60 (q, J = 8.4, 1 H), 4.25 (q-like m, 1 H), 4.14 (d, J = 10.7, 1 H), 4.04-3.82 (m, 3 H), 3.73 (t, J ca. 8.5, 1 H), 3.55 (s, 2 H), 3.24 (d, J = 7.8, 2 H), 3.09 25 (t, J = 9.5, 1 H), 2.99 (s, 3 H), 2.67 (s, 3 H), 2.26 (m, 1 H), 2.15 (t, J = 7.2, 2 H), 2.09 (m, 1 H), 1.51 (t-like m, 2 H), 1.24 (s, 12 H), 0.85 (t, J = 6.6, 3 H). 30 Core 11: Synthesis of Ex.186 on solid support (Scheme 29) Synthesis of amine 139 WO 2011/015241 PCT/EP2009/060168 250 A solution of Ex.181 (2.0 g, 3.2 mmol) in MeOH (200 mL) was hydrogenated for 3 h at room temperature and at normal pressure in the presence of palladium hydroxide on activated charcoal (15-20% Pd, moistened with 50% H 2 0; 400 mg) . The mixture was 5 filtered through a pad of celite. The residue was washed (MeOH). The combined filtrate and washings were concentrated and dried i.v. to give the corresponding amine (1.57 g), which was dissolved in CH 2 Cl2 (8 mL) and treated with sat. aqueous NaHCO 3 solution (2.9 mL) and allyl chloroformate (0.36 mL, 3.43 10 mmol). The mixture was stirred at room temperature for 2 h. The organic phase was separated and concentrated. Purification of the residue by FC (EtOAc) afforded the allyl carbamate 138 (1.65 g, 92%). TBAF solution (1 M in THF, 7 mL, 7 mmol) was added at 0'C to a 15 solution of 138 (1.29 g, 2.24 mmol) in THF (53 mL). The solution was stirred at 0 0 C to room temperature for 3 h and concentrated. The residue was distributed between CH2Cl 9 and sat. aq. NaHCO 3 solution. The aqueous phase was separated and extracted with CH 2 Cl2. The combined organic phase was dried 20 (NeaSO4), filtered and concentrated. The residue was dissolved in CH 2 Cl 2 (10 mL) and treated for 20 min with 25% aq. HCl solution (0.29 mL). The volatiles were evaporated and the residue was dried i.v. to afford 139'HCl (1.14 g; contaminated with ca 15% tetrabutylammonium salt and used without further 25 purification; yield ca 90%) Data of 139-HCl: C22H 30
N
4 0 5 HCl (430.5, free base) . LC-MS (method 4a): Rt = 1.22 (92), 431.3 [M-H]. 30 Synthesis of the resin 140 DFPE polystyrene (1% DVB, 100-200 mesh, loading 0.89 mmol/g; 200 mg, 0.178 mmol) was swollen in DCE (2 mL) for 1 h. The resin was filtered. A solution of amine hydrochloride 139'HCl (ca 85% w/w, 166 mg, 0.303 mmol) in DCE (1.33 mL) and trimethyl 35 orthoformate (0.66 mL, 6.02 mmol) were added. The resin was shaken for 1 h at room temperature, followed by the addition of WO 2011/015241 PCT/EP2009/060168 251 sodium triacetoxyborohydride (75 mg, 0.356 mmol). The mixture was shaken for 15 h and the resin was filtered. The resin was successively washed three times each with DMF, 10% i-Pr 9 NEt in DMF, DMF, CH 2 C1 2 and dried i.v. to afford resin 140 (293 mg) 5 Synthesis of the resin 141 1st Acid coupling step: The resin 140 (loading 0.77 mmol/g; 50 mg, 0.038 mmol) was swollen in DMF (1 mL) for 30 min and 10 filtered. CH 2 C1 2 (0.5 mL), DMF (0.5 mL), 2-naphthylacetic acid (65 mg, 0.35 mmol), i-Pr 2 NEt (0.13 mL, 0.76 mmol) and HATU (144 mg, 0.38 mmol) were successively added. The resin was shaken for 1 h, filtered and washed with DMF. CH>C1 2 (0.5 mL), DMF (0.5 mL) 2-naphthylacetic acid (65 mg, 0.35 mmol), i-Pr 2 NEt 15 (0.13 mL, 0.76 mmol) and then HATU (144 mg, 0.38 mmol) were added to the resin. The mixture was shaken for 1 h and filtered. The resin was washed three times with DMF and two times with CH 0 Cl2. Cleavage of the Alloc group: CH2ClO (1 mL), phenylsilane (41 20 mg, 0.375 mmol) and Pd(PPh 3 )4 (9 mg) were added to the resin. The mixture was shaken for 15 min and filtered. The resin was washed with CH 2 C12 and treated again for 15 min with CH2Cl 9 (1 mL), phenylsilane (41 mg, 0.375 mmol) and Pd(PPh3)4 (9 mg). The resin was filtered, washed three times each with CH2Cl 2 , DMF 25 and twice with MeOH and CH2C12. 2nd Acid coupling step: DMF (0.5 mL), CH 2 Cl 2 (1 mL), 2 naphthylacetic acid (70 mg, 0.375 mmol), i-Pr 9 NEt (0.13 mL, 0.75 mmol) and PyBOP (195 mg, 0.375 mmol) were added to the resin. The mixture was shaken for 1 h and filtered. The resin 30 was washed three times each with DMF and CH2Clg to afford resin 141, which was immediately used in the next step. Release of the amide Ex.186 35 The resin 141 was treated with 20% TFA in CH 2 Cl2 (1 mL) for 10 min, filtered and washed with CH2Cl2. The resin was treated WO 2011/015241 PCT/EP2009/060168 252 again for 10 min with 20% TFA in CH 2 Cl2 (1 mL), filtered and washed three times with CH2Cl 2 . The combined filtrates and washings were concentrated. The residue was treated with CH 3 CN, evaporated and dried i.v. Purification of the crude product by 5 prep. HPLC, method 3, afforded Ex.186 (11 mg, yield: overall 32% based on 139). Data of Ex.186: C 42
H
42
N
4 0 5 (682.8). LC-MS (method 4a) : Re = 2.26 (98). 'H-NMR (DMSO-d 6 ) : 8.38 (d, J = 7.0, 2 H), 7.91-7.69 (m, 8 H), 7.54-7.27 (m, 7 H), 7.03 (dd, J = 1.5, 8.2, 1 H), 6.86-6.82 10 (m, 2 H), 4.94 (d, J = 12.7, 1 H), 4.19 (t, J = 8.6, 1 H), 4.11-3.94 (m, 3 H), 3.71 (dd, J = 9.2, 16.5, 1 H), 3.62 (s, 2 H), 3.58 (s, 2 H), 3.08 (m, 1 H), 2.89 (m, 1 H), 2.89 (s, 3 H), 2.5 (m, 1 H, superimposed by DMSO-d signal), 2.30 (m, 1 H), 2.14 (q-like m, 1 H), 1.64-1.49 (m, 2 H), 1.34 (m, 1 H), 1.14 15 (m, 1 H). The 'H-NMR spectrum is identical with the spectrum of the sample prepared in solution, cf. Table 29 WO 2011/015241 PCT/EP2009/060168 253 a) 0H F0 x 0 I~~o I ' )0 4 4) - HO 1 0 H1 H >1 m -4-) 0 0 u ( I -Q rA 0 Z - 1 C\ 0q mN (N 0 ( v- V P0 00 N (Nt 0 uN 0 N i 0 0 (N1 0 >vi 0 0 No Q (N - d -- I.) 0l H NN EH a) q) -P~ U03 4A Nd 0) $a I u 311 CI (1) 1 0 a) V(N 0 -- 1 Nd oC 01 U 0 (N 0 H H 2_ 0N (I ) 0 V vN - - U 0( (N (N 0 >(O i - (N H (D( ( V~ -0 (N -0 cC a4 V ( 5 0 0 (N 0 rl q X ~ ~ Q - NOV 0N a) 0 0 *C bI I I) I N LO (NO V (N C-) 4-) ( (N 0 I - 0 ( C (N00 ( 0 - ( ( 0 I u- 1) 4)Z ( U 0l 0 xx t44] 0 Z 00 '1 0 Z 0 0 V4 0~ oE-1 U UE (N LO WO 2011/015241 PCT/EP2009/060168 254 2 O\ OO LOO1 .H F2H t t w0 .H (1d 0zL 7 L 04A 0 02 0( 00 H 4( (4H )( H H 01 (Y)( H 0 g g1 01(5( b) H 0 (9() H4 N 0O 01 c O l 0= 0 0 H- 1,.1 8- 12 0) H r(N (N ) 0 42424 WO 2011/015241 PCT/EP2009/060168 255 -1 H p.c o o do W do o o N N CQ I- N - -H -H -H '- '- H 4 4 0 0 H H .H ti (N (N (N ci u -P 1 1 r -1 'O 1 O' -1- ( -1 f - C -' C ) ( ~ ~ ~ d 0 rd a4 -4a 4a 4a H 4 4 V4 14 1F -14 O t. . .t > +r1 r-1 4 1- 4 r- 2 0 | | HP (d u ci) (I) (I) Ht1 D .1 D Q 01 .- l >11 (Y 1-~C 1. o 1. m 1. D 4.H -- 1 N- N L) 0 1V C14 0 ) -5 -5 -5 -5 H n . z O z 0U C'NC) CN) WO 2011/015241 PCT/EP2009/060168 256 oPo W oPo W ~ oP do do HH H H 0t a -- OLf LC too 0
-
.H (d 0 ZL 24 - 0 0 (1 A) Cd - -7 u q -H o o o H -H -HO 0 4 H 44 P 0 00 4 --- | cd 4 -i 04 - RI OIn)t I Q) -lE ( 4 HHH - - O >iH CddU | C 0 - D> 4 (Dac- t - I 0 Z i 4,) CZ z 0 4 (9 0 -H) (d H C z 0 I CD o O >1 0 4 H H 4) z 0 H P4 H H1 N N co xo N 4' zz = o~~= N CJ N N ' 0z401 WO 2011/015241 PCT/EP2009/060168 257 W ~ W ~ W ~ oPo W ~ oP op oPo () N O- m 4-)00 0 0 Q 0 N 0 1 H HP D4 7 a 4 a14 CICL (d 0 o <. - C) o) r o o o r-r S 0 z 0 0 0 0 0 0 H - - 4 4-4 -N - 4 H ) a) qa) W a)aD) a) 444 ) w rd 2 a)2 H a a) 4 .5t . 4 C 4 4 . 5 C -i -1 1 5 -1 -1 S- - - 4 > (D .1 >1H H 4 a rl 42 4 2 1 H (aU 2 (U>1 0 *5o 4) QL) 04 r:4 05 4 5 5 4- a4)0- 404 a) z H 0 - L H O p U 44 4 x (U0 4-)44 4-) c ( - --. ne H H 4-' (1U Ml -Z C') jq mL Tz C2 00C WO 2011/015241 PCT/EP2009/060168 258 tH v -H -H vH co) vH I-- QQ 0) [- c p 1-0 'lv ) ( 0) H F ) 0E-l El E to 0 S0 u Q) t t0 o A~ 0 0 0 0 0 0 NH -P u 04 C) -0 0 D9) 1 >, 14 - (D (D V4 u -vH C v-C > v-H t vC 0 Cr1 H) 41 V: 0 -H tV u~ 9 () v-C 0 (-C -v- _1 u q)7 0 u ~ 04 Z ( Fi I (9 4 .H -N CO 4- v- x' C'x 4-)) CD =<) Z- v-Hv-Hv 4 0 0 Cfl N ZD 0 T Z) 0 C-) =Y r - 00 - 1 WO 2011/015241 PCT/EP2009/060168 259 H (0 H 0 z AH 4-) 44a) z1- 'd z z (0 z 0 0 0 0 o 4- - ) -Cg 4- ) ) 4-) -- ) 0 (D) u3~ u2~ (Da r bi 0 0 0 0 C)5 td 1a01 > ) tC 0( t I t t- H 1 4- 4J 4-) 4-a) Y) H >) a)0 .H -1 04 A1 >(03 N1 C A4 a) 4-) 0P~ CO 4-)~ 4-)- a a)aa Cz A C (N 0,--A ( 0 -01 0- OL WO 2011/015241 PCT/EP2009/060168 260 HrdZ (Urd ) 01 - - 0H O) (I) H H O4 -r- | -1o o - rd 1 0 P 4 04-J > zN-1 C S - O 1I 4 d - - -_ -r H- cd d 2-? >.'- z N t- -- o o. 0- 0 u 4- 7 7 > 5 a) .p4-) r C rd > ~ j 014 d ~ -4- C )t OmZI ZI H D H-- -P - N Et Z 4- D z1 (N 4-)Z L n4 I $a 0 \ N m 4-) 44-) q) (N 4--r m r W) 0 o 4-) p4 .H 'ILO LOLOLc P 0 0 4--) mm _mq 41)4- X x '0U 0- 5:iri 4 q o w 0 0 LA 0 0 C) C) t 4 o o 4JO WO 2011/015241 PCT/EP2009/060168 261 0 G ( N (N (0N N (N I 0 cjn 4-i -P ~ -d4 -P -P P- "-I +i C') C') -Pj 0 c c o 0 0 0) 0 0 on o 0 0n 0- 0 zz z z 09 (ZT N m> CD -c) (n (n 9 C Q ) N ) N 0 n 0 u o q Z QN Z2:: Z2: lI Q)0= 0\ uD 0 -zZ0 LO 0 Iz )n _ E-1 WO 2011/015241 PCT/EP2009/060168 262 0 A(N N (N (N N (N N (N I 0 .0 0 .0 .0 0 0 .0 I -P -W -P 0 C) 090 c) (v)( 0H 09 cv- C99(N( 14 04) 00 0-) 0 co 0 0 90 N 0 I- D C oo c/I0 d 09 9 09 09 0 v- Fo 094 F-4 F04 F-094F4 0Y Y)3 09 09 9 09 0 09 0 LO CC) Q 09 (N ( N (N N09 - ZOT zm zm z - _ 0 0 0 0I 1.0 oZ 0O H z H H H H -Z \ CY) LO OD WO 2011/015241 PCT/EP2009/060168 263 0 3I 0 + 04T 09 0 ~ N CY) (n( 0 0 0 0.0 () (N (N N m 0 m9 0 0 0 0 0 0 0 0 0 r- 0 0I-) L 0 C Q itS 0) 00 H N O I-- I oY cn Y)IY 04 0 0 0 0 0 0 0 LO9 .0) 0990 (N W9 r 09 0) 09 (N (N (N (N 0! 9(N 0 WO 2011/015241 PCT/EP2009/060168 264 0 1/ 4-) 4-) 4-) 4-) 4-) 4-) 4-) 4-) + N mM 0 GN C(N C5) C"(N(N 14 LO- C (N 0- (N ( (Y) E-1 t 0 v N( N ( N( N ( (N (N Q0 (N Q0Q0Q0
-I
OD CD CC) v-H ODH 0- 0- v-H v-H00 o (Y" N(N (DO 7v (n r/ (4( (7N (O CD v- ( HY I(N ((N (N (N (N P4 09 0N0 9N ( U 00 0 0 Zr 02 U.)~~C :ZI) _=LO~_= _ = _ __K 0 .-4 lvi C'. U.) CiCiC WO 2011/015241 PCT/EP2009/060168 265 0 A(N N (N N (N (N (N (N N I -P -W P 0 10 09 09 0 0 9 N 0 14 4 ~ 0 09) 0) I- 0 09 09 0) -P 0HY n c o C)c Y 000 1 0 0 0 0 0 0 0 0 0 000 0 0 0 0 0 0 0 09 0) 09) C9 09 0) 90 (Y) N (N 09 (N (N (N 09 09 0 ZI Zr = o - \ Z , >=o'</ OD m 0 .- 1 N Cf) T LO C r~ rCI 0 0 0 -0 10 WO 2011/015241 PCT/EP2009/060168 266 0 0/ ~ 0 0 0 0 (1) W D + V L Lf-) LO Lfl 09 9) 0 CC) 0D 09) OD( 0 14 04 ) 0 9 J 09 09 09 O 049 0 0Q 0 0 0 00 0 0 Q 0 Q0 0r 0 Iz I z z z 0 01 1 1 1 1 1 YZ ZI ZT 00 / 0o -e o -Z 0/ 0 0 0 z zI I' f 0 OD m -1 xq C -0 10 OL O WO 2011/015241 PCT/EP2009/060168 267 (N 0
-
0 - 0 0~ 4i u 00 -P-P0 c Iv--H 00 -p (N -i N 0 -10Q 4- 1 0 _ I Uv _p OO L 0 0 -v- LO 0 v- d 0 1 0 4 ( -1 (N - 1 v-H .- >1 4 (N -H, 1 0 01 a 0 01 0 H - 04 1 v- I4 W v 0H G0 >-v >1 Uv >v 0H I -HO0 C+ u, ovi 0 0 I -- -- I v- _ - $i Z 1 1 0 1 0 (N q) -, >10 v-H 0- D 4J (d 'i u 0 u CD>10v- 0 >1 (N I0 0 -0 C14~ C) 0 - v- 0 -0 - - 0 0P 4-) 0 ' I 0 -Q 0 0LH 0 0l (D 04 0 - 0 0 0 -0 0 (I $aN t1 (oC 0 1 N( 0 0 0 0 0 4-)vH - A 4) 0 0, -A) v- (3 -A GD D 0 0 I 0 0 I 0 0 P I (N 0 0 0 0 vH 03 0 E- to ( v- -C vH H ) 4 C) v - ,1 4-) - ( o O LO v-v- 0 N 0 - N 01 LO (d 0- I- (dv m I- (N 0 d( o (0 C- X-v X~ N ~ (N X 0f G)N 0 4~ -- 0 (N v- 0 0 N OH - (H - ( o 0 N 0 - -- 0 ( 'l Q - () -1 = ( > 0z I -I 0 0 (\ o o (N * 1 ( co = (N N ( N ( N mN ( H (N -y H ( z (N 14 N N ( (4 (N 0) -P(N 0 (N 0~ a4 ( 0 4 0 0Z z4 u 0 0) LO LO Z0 E-19 WO 2011/015241 PCT/EP2009/060168 268 o I I N O O I I 1 0 0 1-I XI I - H o LO1 0O L H H C - | H1 I9 I>9 J m I 1 - 1 H 0 4O 1 I H C 2 H H 4 N 2 O rI O rI 11C C r - I d I 9 H O r O O >1 C O1 H Ln H H -HC I I - 1 t O - 1 C C 'O HZ ' I I I -- I r H z ' 0 -H O r- H 0 I - H C -C C >1 H >1 m 0 0 C S - r S I I 0 0 >C) 1 t C C I C C cN CO 0 I =I I - 01 C 4 - N C 0 H 4 >H o1 -- -H '-t 0 t'0 - H - 1 H- | -- 0L r-H 0 >9 't rl '~ t | | - -H - - 01 r-|H |9 - -n H r- | rd | | r 0 (N 1 (N H v-) >9 Hd (N LMC - - C C C- r I |I | | | >1 '- Cr I 01 I O01 I On O x - O! > , 0 O m O 0 CO - CIr1r1 - 0 0 H'1 r-I 0 - U 0 C l 0 C 4 -2 0 - ' H - - - H H OH C O H t H C t I C -t 4 H n - H4 H 4- H n 0 4 42) 0 4 -H >9 r0 H4 H-- I S 01 75 a S M - I n 'd _ '1 >0 (d O 0, M LO 1 r-1 o faU H C N 2CS4 0 >95 S C- C = H CW I LC )I C C C 4 C d C rd -H C 0 (N C , C L1 >9r C ( 9 C C m 't , 42 I mC -+Hr- mO -a 1 0 -H 01 0 - 0 H C 0 I C 0 H I I9-1 H O I 4 2 C I ..Q 0 C t- I C, (N I rC I - C 4 - C 0 01 CI 2 CL- C ) 0 C -1 O H C C) H C C - C N 4 -) S C ) 1 - H -H m C 4 -H > I H->9 I rd I I | | | | >9 >9C H- - C H - C P C HH - H H H m H N C H 0 H I I H C H H C r Hr ( I H >901 H -H 01 H C I -I 01 -L 0 - 0 0 I - 0 I 4 -- I H I 0 On HO 0 I 0 O p C liz C C 42 C T 9 - C 0 C I I H H mH H 42 -H 0 >, -H 5 a- -H 0 H -H H- >, - H - 01 >, H- 01 >, C 2 C) C 4 2 - -H - C C - C) I 42 C >1 - -) 0 - H I -C (U 0 C Ct '0 C 001 C 01 C 01 rC t0 01 rm CtO "t t- - OHr- tO H- C)"O - N C - N - C - C r I - C H - rd L C r C rd C H r C C t 4 -1 H t 4 (N (N 4 -1 H N 42 t- 42 - s H I - -H C 0 C I 0 C '- H C I - C 0 0 C 01 CI >90 CI -H '~0 0 1 tO C | - C L0 - C C t'~ ( ) C &4 H - M42 C 01p H- I 01 9 r- 1 H H- r- 1 P -H I 01 -H 1 rC - 1 Cd Cd C C I CG 0 I H- C I H- C S rC C S - C I - C H 01 H- -~ 01 H- -- , - - H r- Cr 01 H Cr (N 0 (N (N 0 > U H O -O O C O O 00 C) H H C) H I N - I N C - >1 C - >1 C H >1 C H >>1 - >9>90 C-C C 42 01 -H 01 ) -H - C -H - ) 42 01 C 42 N C I N C C H- Ce S H- rC S0 Cd S01 Cd C H- rm 4 042 (N O042 S - N C - N Cd - N Cd - N - N C H - I H H m CdH c H o 1 C-I o d d m md C eN 0 C cN -r H H >, i . H >, , .H > , .H - -i H 42 - C 42 - C1 4 - C1 " E- C 4 (N C I - C ' I - 0 I I N 4 C (N 2 C -4 C -42 c cm 42 - o 4-4 0 (N H- rC ) H- rd C) 01 C C O C r I H- rd I H- s - H rH-1 -- N Ca - C rC - N rC - N - - N (N -0 H 4-1 01 - H C r O - 1 0 -- 0 0 - H C - C - I o I H N ' I N I - N I - N d -I N I - I LH - H (N - C (N - C CN (N C (N CN C 0 - C >9LO - LO I O1 C I 0 C I I C I I C r-H O (I I I r, I I -, H 42 H 42 042 - 042 -H 4 - H C) -H C - r- Q x - - - O Q - - C -Q 0 - , - 0 - U i 0 - i j 01 (N C 01 (N C NC0 NH0 (D N C0 42, H JC42 01 - H 01 - H 1 *n H 0 H - - -, 01 4 2 > - 01 42 0 c- rH 01 - H C - H O- - - 01 - H C 4( H C (N 03 - r- 0 N r- 0 - r- 0 I r- r ( - 0 H 0 0I *H 0 -01 H-01 H-1 01 H 0- 1 01 -01 H- Hu H- t cH H 01 H - 0 -) - H H-1 0 H ' 0 01 0 01 - -I -1 0 - 01 Q-1 - ' - 0 - I 01 H 0-1 1 O (N - r - (N - I - (N - I ( - - I - r- ( - c >k (N e- l (N r C (N r-, C - r-, N - r-, I1 (N r- C C -- >1 - > 01 O -Z ZZ I at/ z/ -z / \ / \ 0 zz WO 2011/015241 PCT/EP2009/060168 269 0 |1 -1l 1- O r 1 0 O L L - 0 09 H H 44) 09 N -1 -, 4] Q) (o 0I C - L-) - r rH ,C Hr 9 42 I -- t I I ' ~0 1 -- t I ' 0 -H- H - OC C OC - -r- LO - O OI r S O) -1 H - - - O H > H 0 >0Z HH wo -1 - 4rd M H O- U ' - 0 0 -1 4N 0 H -H 0 - 0 -H 0 L) n 0 0 H c 0 c c - - r Q 0 I -H L H r | '-- 1 a '- 0d t rd I t C N I '-- -1 m H 0 Od .H H4 01 4 ) Hz C4 >9 t4 Z 71 t l r -l H I - H o I Hl H 4 H - - Q Q-Q1 C ~ I 1 M~ 4 v-H -1 md 19 C I (3) 1 I 1 M~ r 0 X v-H I 0 0 Q 0 1 0 H 0 - C - N 0 0 Q 0 0 I 4 C OH - > H St O '- t) 0 i H - mr - 1 cd -- 0 01 M 0 0 0 11 I 4 - 0 __I -Q- I x I rd I I (d H i -- - - 0 m 0 c1 u E 0 > 5 0 U 0 cd 0 4- I 55l 0 eN 0 O H 0 r-, c Q -H 0> I El 0> I | 2. r C '-' N ,Q~ I N H I 0 I m 0 - H OH H L | r - - O 0 1 0 0 >1 -i > ' -u -I - H H Z r S H I d l I L LO - | m HI 0 | | LO cd 0 t' U t -1 C 4- I F (N - V 4-1 rH ) -0 - C H - l I - > I 0 Z 0 I Z r -' C I C 0 Z 0 > L -u 04 ~, 0 H , L - | I -1 -H Lr) 1- -H C - , , > 0 C 0d 0 I H l H-I 0 Z H U H H C H I -l 0 r Q U -H C) C U H 0 rd I 0 -. I - s I - U 4 0 rd U I - S ( H L L ~ 'I ' ~ - ~, c '- 1 i ) 5 q E Cd t S OH Cd OH d i u-t- L) m 0 i - O Ot 0 4 - r H -1 H -H - - - H t ( S >i H __ I H - C H H - C >N > I Z H I H o H I S r, r r H ) 5 H C 4 I H H >94 0 Q 0 OH- 0 o M C - X - U OH H I I oo I t 0 H , I 0 0 0 0 C V H I 0 N V H N CtD I H t ( H H H H H H 1 t I H I - - 1 H - 0 C > 0 q U >0 0 0 C > '- q 0 m C I -t -H- 4 - -H 4 m> >1 4 0> >1 O0 . - H C 4 -H C H -H I C) C I C V - U W - C C I O) 4O 4 C -H - U H ((I) O Cd m U o rd ) o (0 H- d 0 C Id m 0 M V -- m Cd c> ' (d N d1 N m t S o ' (d H-I ' I -1 rd - a rd - > rd - C 0 d a -1 H C rd H - Cd 1 4 0 - 4 0 - H 0 - H H - 4 - ' ' 4 > (N H -0 C CC0 C C LI C O 1 >i0> C I 0 C H- C H- I -- I H-1 -- I - 4 -- I - 1 4 H r (N ' ( 4 - V I - QA S - Ca S ) Cd 5 C) d 4y Q H-1 I q V H-1 Q (N O) 0 G ( 0 a - N r0 - N ( ( 0 - r 0 H 0 I H- H- H- - H H- (N 0 H- cN 0 S H- H- > 0> H -r- - H O - C) >i - C al I N > I N -r- - C) I H- C '-0 U M1 (N >4 ,CN >it 0C Ct, 0 Ct' (N >1O - >i - H >i O H C) 4 H C 4U N V 4& N C - H ) k1 O3 C1 - U 2 - r 01 l m rd ) 0 O . CD 0 ,.Q I - rd O Hr- rd C(N 3 Cd H- H- N 5 H- N 5 -r- '-, -r- '- N H- N D - N '- - N 4-1 Hr- 1 r -H H- rd -H Mi e -H ki e '- Hr- 1 r H- C' rm - 0o Cd I - -H t- - Hn '- H- '- 4 Hr-I - * H 4-1 H- -H '-' - -H Lf O L| -' O L| - | - - | - | 0 L| | - | | L H- H- 42 I Hr-I I Cl > I r') N Hr- 42 L) CN r-| H 4 I - rd (N - rd e H- - (N H- - I - rd H- H- rd H- oD C 03 N '- 0> N '- - - - 0> N I - N I - N C! - 0 ~- - O ~- 0o -- 0 - /) - 0 - H- 0 - C' 0 Md o N 0 N I - H | - r-I Crd N 0 H N U - N 03 - C (N - C eN L) '-- (N LC) '- 03 - C rd - C(d N C r- > ) I > I I r-, I I r-, Hr- > ) 0 > O C D G> I V - - Q - - - - -I - U .- - H C - ,Q H- H- .Q H- 0 ,Q 0 Q 0 k - >1 i ) >i I 0 - - - - N H - (N rd - N Cd , H (i , H H - (N ) 0) C O 0 CN H 0 H 0- C v > 4-) c- 4c - H 0 H H - r-1 H H H 0 CN > - (N > - S ~- - 5 0- (NC > - - > -42 r& (N I - 0 I - U *H 0 U *H 0 N I - 0 > - U I ol , H! C co H t H H t H - N - 4-(N C) 1 H O Hr I 0 H-I 0 H 0 H - 0 M - N M1 - (N 1 0 H - - , *H -~ 0 *H '- ) H- kl U) H- kl ~- *Hc '' o I l r- N l - ( - >1 cN - >1i I ] - I r- r Cn 4 ) - 4 C - - - Q. U 4 c u i LO u C~ , 0 ZI : ZI: zr Z= -z -z -z zE / 0 0 0 0 0 Z Lo I-2z CI Ho H- ODI H H 0 zu WO 2011/015241 PCT/EP2009/060168 270 0 I m (NI -r- 0 I- L Cn - H L 44 (D 0 0 S 42 0 - 0 o H d I r-1 O H [r 0 m 00 I 1- 0 0 H O S 4-) rd 4 A '' H (NI -C L H -H H O~ N O d rd 0 2 O 6 I [(NO C QI O- 4O H H dii S I 0d ,Q v- O H I -H O M ( 0 - v-HM (N -1 . i 0 0 r 4 -1 11 42 t4 -1 M O4 - - H M N C 0 cI1 ( oi -d a O e O r Ot t -'-' rd '-' a- 4 m 0 H ( (N (N 0 S O v-H 0 d (- H r -H I O H HI) H 0 H O H 0 O4 0I di (N 0i di Z 0 r Io 0 O O d ,Q4 9-| LC : O ,HO| 9| L C - 0 u O0 >1I - 1 > M O I- =i r o X I J) t I 4 v-I -iII 0l do -H4 2 0 ) H rH 0 0 | | H - 0 0 r-| 0 (HO 0 t S H (N oN ( S N oe H N O m4 |01 T o | 0 1 H 3 L- Q o '-' I |0 r0 -0 O N Cd t di - O -0 H 0 I O - 0 -d H H 0 H X L( - H H 0 H -H -Q a 4 2 H - 0 0 H- 0 >1 0 Q LCi Ia HO 0| 0 - -H Zl ( 0 0 I 1 0 O -C- 0 0 2 0 0l - . 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H N N - U H ' I I 0 (U 1 I 0 - I >1 I [' ( I r -- - V -- H V -- 2 0 -- -H 0 -- 4 0 -- - V -- -- C O -, U2 - -, ( U -| ) H U) N H Uf) V 9 ,U - I N H-( (0909 N Cm 0 r >10 N d 0 d (N N >1 r- 9 H - 09 . H- - Cl H- I | C) H- - Cl H- - - - H (N 0[ - 09 - n >1 -0 >1 - >1 090[ - t U] 09 - r2 0'9 -Ur> l>1 pa rU 0- O rU) |>1 pa r) I - r> -r- 0 0 H 0 H 0 Hr I H V I H 0 0 H- O 0 -H® -H4-2 (n H I 09 -P H : 42 x.H N 0 0 - -1 - rH - C LO - ' LO - C LO - O H - l C) -- '9 0 09 '-- 0. - 0. N - -0. Os - . -r- '-- C)E El N - , - N9 - (N rd . 09 I 0. 0 N 0 09 5i e- 0 1 09~~~~- C4 (NC1H1HNH4 )- 00 / \ -Z -Z -Z/\ /\ V .n W r tO om o OO 0N %D N D% -z- WO 2011/015241 PCT/EP2009/060168 286 I I I I I c -l I .C . 'o - 0 Oi H 'H rH >1 >1 >1 H X -3 0 0aO 00 D i Q) z -m -1 -0 o(aC o a o o a o o1 0 oC 4 I u ), I - d Cl -0 =C m3 I I ro I I "i I I ,a 0 -1 - Ho H - =i G ( N ,) '-I - 1 1 H I H -H - -H ' L O -| H 0 r-| O 1 1 CO O I I o '-1 >1 >1 td >1 '~ H H Z - H N N I N S I C S o 0 > 1H 0 |H N m (Y 5o co 5o 5 In m 4 N M 4 N -0 t r-1 t t 4-1 4 0 v 0 1 m = 5 O 5 O 5 - 0 >1 c- 1- C m m C S t t- H S H r- H H C 4 t- St t St 0 L H 0 O 0 O 0 O > >5 -1 0 H > I5 I >1 C - C O C O H O C C C C | C- C | C- m H C) -N - >1 C) - >1 >-1 - >1 '-, t- -C H C) - H ) -N >1 ~ ~ ~ ~ ~ ~> mo 5, L|L'- k - | C -- G - O N m O n m ,H r 0 0 c C c |C| u | | H 0 0 t r 0 t C 0 - t 4 I CN] I I C I m H - t -H t 4 -5 t m4 i 0\ CD H H H C H | H L0 | | N Cd C 0 | C\ 0 Id t C 4 - - - - | C -- C |-t C | -t C - r N 1 r 4 N H I r- H | 0 o o rI 4 rI MM IC ON H 4 H H t C, H 0 I C 0 1 C I I r-I Q I l = Ii N i rI -I N r-I rI N >13 ) 0 4 H 0 G -] HU - 0 G3 H 01 (1) 4 H H I H I I H S I m C H 0 H HO H QH 4) - I 0 0 C 0 0 N1 0 0 1 1 H- 1 r, - II I | H C - C r-0 C I 0 m 0- 0 C r 'H C I -H r 0 Z o5 > o 4 -4 >1 H -4 o o 0 H 5 0 ( 5 0 I13 C C 0 -W 0 -W I C -P 05 -1 C) > 3 C)53 C -1 ~ L o mn Z C , C U , C H H r r- I I - I C 4- r OH C OH r I $a (D (D Z) I , -i I 3 C - t $a S H N H0 03 H - (D '-Q > 1 [ - U N > o - 0 in 0 (N in 0 (N in 0 (N H 0 - 0 - - 0 0 H I C I I C I I M H 3 0 H 3 0 I 0 ) 1 0Oo I " o I ' m -H6 0 U) 0 -rI H r C \] H t C \ H t a C x H C -rI 0 Cd -- H Cd -- H Cd ZO - > r-1 rd 5 r-1 rd 5 r-1 rd O5 (ON - O1 -0 - 1 H I > O) 4 4 o - 4 4 o r- 4 in r-) I 03 O) I 3 O) I > O) m\] C [ C C 4 C C H C H - C H C] C \ H r-| N C I ) >1 C C) >1 C C) >1 I r-I N r-I 3 N r-I 3 N in - C O m C O m C 5 C C 4 >1 C 4 - C 4 - m 4 4 (N .5l .5 t 5 t 4 4 4 0 5 4 ( 54 (N 5 3 4 O tC4 ,Q i r-4 riO Q4 | -, C cc N 0 N 0 0] N |~ H - C - , C -, N 0 3 t H C 0 H C 0 H o 0 t o C0 - - C t - - N O < - 0 - - > H 4- > H 4- > H I I 0 oI r - 0 <I -0 (N r-, [ lN H C) N H IC ) C (N >1 N (N r-, [ (N r-, N -1 > C rI - N1 rI - (N rI - 1 -r- H C -H >1 C H- >I - O04 C H- C C H- C C H- C Ir '44 |- 04s | O04 0 C - - - N 0 - N 0 - N L - r O r C 0- .d (-- 0 03 C 0 03 C 0 03 C 0- C1 (N - 0 '-'5 (N 0 '-'( I0 -. '- ( N 4 I (N 4 rd (N 4 | >1')- I0 - >'- | Q, ' -O - i r Q i rH CQ in H C - - - -- H I 0l - rI H 0- rI H 0- rI v- 0-, t | | I 4r-I I 0k Cd 0 r-1 ) - C C - C U - C rH C H- rd >1 H- rd C I -- , O C- C O C C O C- - I C I m% 0 - C\] r-> H 4 r-> H 4 r- o 4 -1 | C\ -1-H C\ r-1 0- C\] U) C O - H - E - H [- U) I O ) -H-I O ) C O H 'O HO C > (N - C\ > (N C > (N C 0 H Cr-1 H C- 'O > -H l - ' ) -1H U - H- -- ' - Hr- - O C>l - C - - HI (N '-- 03 - H 03 - H- 03 '- H -- I ( N L I ( N H I H ( -) >1 >1 H - r-, H - r-, H ( N r- - Zl >1 N >1 >1 -\ >1 > -' Ca 0 - CN] - CN] - - (N) - -' I 0a U H a 0 - U) C 0 -zH C - H H -0 - - C -zH ZZ-IIZ-IIZ-I - - f -- l 5 L D O lU)' WO 2011/015241 PCT/EP2009/060168 287 0 N I 0 r A1 0 - 0 - rI 0 A '~ A - 1 1 I 0 I (N rd- r I ,C L L 3 A- (N ULU 03 n |I 0 W -A -o I 0 A I An N Ut I Z - U 01 A - I - 0 -H 03 N 0 0 >1 m W I t A- I 0 > 0 U A A- C (N 0 d o0 LU Q. H t | n trN C U I U >1 -H W I 030 U - I 0 0 t n 4 ) 0 A- r- I A W I d Q V >1 W >1 Lo I I 0 - - A-I - kN U U V 4 LU - ( t U1 t (N 0 N rd I 1 r 0 0 r r-I LO -| | '- 'ur- -|rO WA - - >1 N U 0 - C >1 3 I -, 9 r cl 1C o- - -I -H r1 0 1Cr1 r1 O '0 ,Q - 0 0 - A I I - 0 I r-A 0. - A 0 0 U Ul Ul LU | A- nH 3 t | - O W 03 | -H ' 0 Vt I U - I A O n S A W S I U I |>1 - 1 I (N 0 >1 - U- A - 0 0 (N V At - ' U 0. I - >1 t (N A 03 A 0 W >1>1 A Ct'0 I N 0 U I - U A A >1 Ut " VC ,Ct I n -H Ott' '-' 0 (d N -0O >1 - | 0D H -) r 0 0 S A LU A 03 N A- A- 0 , 0 N '- t 0 U S N U 0d 4-1 - S | r m - 1 0 - A 0 0 0 S 0 0 0 U 0 I t 0d 0> -H r 1 V W - 0 I ' N - t - N H >1 (0 LU A- N I r U | 0 -, H 0 0 >10 0 Ul 0. - V - 1 0 03 4 CA W CA U U 0 Q " Q 4-) 1 I 0 V i U m Ui -0.0 -(0 0 03 U V I H1 1 t 0 - UI 0 0 N 0 0 0 A (N 't GJ r-I V 0 003 LU 0. At 0 0 -0 - r-| r-A 0 H 1 O u U A N N A-03 U 0 - V 4-l C- 1 1deI | s % - C , 4-4 4-14 >1 r-| r-I I - A 0 - A r-I >1 V 0d - I W I 03 U >1 -1 W LU s- | A I r-3 A | | W U A- LU N V. L0 - 0 rd -0.i I n 0 I N A I LO C (N - a I A-1 O ' N V 0 0 I A - - I U C W I A (N I r -1 -1 - -0 s 03 Osr 0 0 0 0 Un 0- A S - U - (N -A Z rA A >1>1 -A A A V - A- U -0 >1 H > 1 U I - U V LU U S I U >1 I [3 >1 (N V t - U LU - 0 A N' 0 V r 0 0 (d 0 , V m , r - 03 0 V At >1 -t ' 0 U ' Ar t V -1 N V C N I N WA 0 V - r 0 >- A- 0d 0 - C N C (N> rd -, V V A- V Ar- V ,V - V --,3 on - C N - - -r 00 C WA r- 0 ) V 03 0 0 - CA 0 -3 U1 Q) r- 1) 6 -0 0) Q r-1 Q C LO r- w -|P' - A 04 - -0 I r 0. W 0 LU 0- U -Q d 0 0 0 t A O m C A 0 0 S A I I - - N rd - A - r -03 A - -| 0 >1 H 0 0 N A (N C n 0 U N 03 U 3 - U - U - , - A A AI N >1 - >1 r-I I >1 I - >1 I (N > 4>1 V N >1 - --- 0 0 L U U 003 U N - U V I '-' V o [3 o N 0 - d 0 Z r- 0 U 0 '-' - r0 V 0 C V - - 0 0V W 0 N I [3 N C - N I A N 0 -A n W LU N 0 Ar r0 0 - 0d 0 0 r-0 A C 4 I - A U (N 03- Ar- Ul 3 -r- A- r- A-- I - -r- -r- I U -r- - A- - V A r - U C - H 4-1 - U 0 0 Ul t N Ul t\ C '' I I - N V 003 V I (N V 0 -I VP - -I >1 - 0 - -i M I | 0 A - 0 LO (d - - 0 I - 0. I A 4N -N N r-A - N 5 0 N N - I N 5 I - O 0 I I O I n 0 - O '-' I t 0 -1 o | 0 N Lo - N - n N I 0 N I ~- LU | - - N - A Z A CA 0 003 -C (N -0C C - 2 -A N - LU I 5 0 I 0 0 r0 0 I 0 0 t H ), - - 0 V - -A VQ m na V - - V - An - V C I A- U 03 - 03 r- A- - r 3 03 5 I 0 W A 0. >1 I ed >1 - 0 0 (N - o N 0d - (N 0 d 0 W 0 U C V A S - A > - A 0 - - -1 A l A A - U - >1 0 ( H C s -1 1 r1 o a -1 s a r- 1 >1 -H r1 - k >1 4-) -00[3 -0O0[ Ar-03 [ - (N>[ - >1 >1SE - A- >1 V S 03 V - 0 0 - - [ 03 I - 0 V LU (0 m >1 0. 0 A C O' A rN - 0 A ON' A r N -1 C I Q ' -1 H O -1 A V -N 03 - A- N * -1 A U U C - A V I I O 0r- -0 A -(- A -OA -,Q V -C LU V (N U - - W '- '-' o - A r1 - r Ui 0. - Ui A- Ui ( - (N 0.- I - r- N U - (N - 0 0 (N 0 t W - >1 - U U0. (N U - V U - >1 -00 - 0 -I V [ 0 Zrzr zr C 2Z r N / Azr /\ - Z / = \ -m- -Z -Z 0 N N l )I WW z xZ xZ xZ N OD ) N N- (N Nr N0 WO 2011/015241 PCT/EP2009/060168 288 -4 O\d 0\ \ \ LH a). 0' H 0 00 0 x0 -1 -) 0) 4-) U 0D 0 4J~0 4 -) a)i Fz4 0 C1 m a 0 u m 0 0, 0 0 ) 0 0 b) H () ) I o l H OD OD OD OD C4 4) H ~~H i a H4 0aH)) a)t0 ) 0 'O LfO () * CD 444 0 * -H 0 CQ) (0 C Cl)= ) 1 x Cl4 0 ow HO CIO~
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Iz Z= - Z=Z N' 0 Ozz o /\ZZ 0 ~08 0~ M: z0 X- N CF LO W r- OD 0x [0) [xl [xl [x) [xl 0l [x(3 WO 2011/015241 PCT/EP2009/060168 290 -I) -I T poP op odo oo ,J, + co oD co 0 U) 0 U) 00oO \ \ .- C.C .-I H (D 0 0 d 0 H -H 4 -H OP -- - H 0 4 Ik rd -r-1 H U2 >1 4 4-4 (DZ . - 1 H sH) aa 0 0 - - - - -A 0 a a a 2 2 H, -H Z m 0 a) 0 u H - u -1 Oa ) H H $4 (d N P LO z L cl 0 o 2 ol 0 0- 41)) WO 2011/015241 PCT/EP2009/060168 291 |n o si.co o o o o o o o | A 0 0 0 0 0 0 0 0 P -P - - P P-P D -( (D (D (D (D (D 1 0 0-) (N mN (N 0" (N tH LO LO LO D Q0 -P rd oo o- -- o o o - o o oD L" L) L L1 L LO nL o 4 o q L O o C) LO C D LO 4 - O m 0 En0 o o> o Q0 zc zD c) c -~ > (N(N N ( r-N CN t-N O Q0 Q0 LO O 0DI I- I- I- LO LO LO Q0 Q0 GD) pD Q0vI 4-i 4-4 O (N 0= (N ( ( o( coF O OD (Y) 0N 0 0D ( 0 01 0l 0r 0 a) O O O m 0) ON (N1 ON z OD WO 2011/015241 PCT/EP2009/060168 292 ca~ 0 -0 Z~ 0 0 0 0 0 0 0 0 0 I -P -(" -C, -C, -C, -0 0 +r4 q) (N qN(N (D (D 1) qN q) + V OL ( 0 L 0 (NI (N (N (NLON N ( >1 cc) (N- CD OD ( ( NN ( 0O 0N (N (N(N (N (
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4 o N (N( ( NN( P4 0 N((N ((N( (N ( 0 o o 0 0 0 0 0 0 0 (N (n (N (N CN(N (N (N (N (N (Nl (N(N(N (N z-O z- z- z o 0' 0 0 m 0 o I cFA 14 0 14C~ WO 2011/015241 PCT/EP2009/060168 293 0 V - I9 aI r T I rd >1 H H 0 H 1 0 4 (N 090 ( o 0 oF) 0 0 1 H H I - H N L I M '0 e 14 (" O O a U) 0 t 0 H I 0 0 H - 0 I + ( 5 ,2 H 0 H 4 H >1 (N S >1 O I d c] -0 4)l (L (Do. 0 1 H o 0 t O -r 4- N O0 - | 0 - - H t 12 - -H42 Q I - - 61 e I k '-I x C c o u N -- 1 -- >2 r Q N O r H H >1 0 5 H 0 0 '-, - H H I - 1 .0 -- | H -) H '- 0 S > I 0 - t >9- N ) | 0 4 I > 0 I 0 ( 0o 0 I I U) 0 '-, r9 H 0 - N H > 0r HN m -H H d1 O - 1 0%a O > 4-) 421 19 > >9 2 0 I -1 - 'C O M , 0 , I0 0 I H 0 H 0 H -H -5-H I 0O H H 0 >9 I | H 0 |9N 0 2-] 0 242 0 C N -4)4I t r-I rd 0 0m - d O 09 0 '0 > '0 L 0 0O 4) H 0 i >1 -~ H O OH t 0>9 t HG) tO '0 LI -1 4-0 9L 4-1 I 9- P 4-1 L0 S0 H - t a I H - I H I I H 0 4 20 Lo r-| 0 L- x Lo P4 0, 1 0 n > + > > 4 01 - 0- > I 0 rI - H I I I 0 00 4) H 0P 4 ) 00 4) 0 -0 0 O H M H G 0 H O |-0 N 0 >, 0 - 0 O H 0 0 M 1 0 H 0 0 d 0 N 4 0 -2 0 ( 4 o - H OC 0 -P 4) OH 4) (1] - 4-] 04(-] ( -- Q0 N ,Q r-P m 1 No >1 -, o k O 1 H x 0 - 0 I H I r9 0 I I H H| 0 00 0 (N H 0 (N - 0 (N o4 -H H H H - H > 0 H O ---- cd N I o' N N s C v s o-00 Q - Q O Q I - N I >1 r- X - - - z - I I 'z -C -0 H - 0 9 - 4 H - 1 m 2 H - -0 -H 09-I - 09 0 I c 09 01 I - >, H 0 >H -H c > 0 LO - C_ N 4- 4- r_ 4- -0 - O ' - & -l O 00 ( - H 4 - H - - -H O H >1 r4. > o 0- 0 0 Q (o - Q -- I - - ,c >0 9 -1 0 L- - 0 H 09 H 49 - H 0 N -0-0 0 - -0 -00 - H 4 - N I l09 N ( - N >N >1 0 - (N 0 N -0- (N 0 - 0 -a - z-m H H/4 2 4 \ 0 \ O O - O o 44 00 0 044 0 44 00i rz00 04 00 4r) 4 LO %Dr o( 0 ~~~ a)00 9 O O N t r 0 0) U) U UE-1 WO 2011/015241 PCT/EP2009/060168 294 I I - I I N H 0 x I I H | C A A C O 0 0 Hw, 0 .- >1 0Y N ( C 0 -Q0 0 t4 W 0 N I A ( rN (N 4 N t " N '-t - r- I -H t u~ >, '-- r-wa - 0e N Aa, O- 1I -C O N S N 0 O t 0 > O 2 o -0 o - 0 N I N 0 -H i LO - I ,Q H Q o O A N 't rN LO N ( - 0 A- -r- - A- (N -r- - Z | O Nd 0 A o ( N >1 >1 A A A - A U H U >1 4- ' C a O >1 A - I - >I o I 0 N - I N a) 0 N >1 C A O U rN CO A- t 42, Z t- (N N 42 ( t 42 A A - d N H 0 H Ga LO -H >1 I 0 , 0 -4t H 42 - I CO N rd (N S Nd 0 S A o a >1 N O N - N -.- o2 M r ! Ij rd I ( rI rd , d r: -- I[ - A- LcO (N N 0 C Z N 0 AP I t N 0 A 0 > ( - >1 N I A N A N ( 0 N N H - -HN 0 Lo o T | o - - | 0 0 1 N | CO 42 rd I I 42 - 04 I 0 I CN 0 4 24 A N N - N N H : I 1 LN A A O t ' N 4 - t -- N 0 >1 in N 0 r A GA I 0 Nt A r 0 N ,C - U >1 Q Q 4N '-C t U H A - N N 0 4 0. I A t I A ( O ' I DI N -0 | | C N N A A >, N A > - >1 - - -1 Z O NA 0 N 42 I A 42 U A, aiLn | mO A | A a A N,4 | H 0 I 4 N I u I I C A I CO - O I 0 _ N A (0 O S 0 0 Si n 4A 0 I - ( Q) ( A q) i0 CO 42 U -I U 0 Ud 42 - C U I d - U 4 I IO H O - Ut) CO CO t CO L t r-| A t | - N 5 - -i - NA 0 N S - N 42 CO N A I A | >t 4 - '- - (D 4H) CO 42 42 - A ,t C A 0N 0 0 > 0 >'~ t 0 (N A 0 N O (N I 0" G) H ( -A 0 Ud -A |i H -I 1 0 '- r - t N I A ' N I >1' 4 - N > 42 CO in H N '-0 y N O 0 - 0 CO A 0 t 0 - o H A - 0 CO A 0 H I U A A - A4 C U~0i -- 2 A U [ - C [0 N C -0H C CO 0 N | 1 '--' 0-, CO U A A A I U - - U - A N N 0 U - O A N O N O ,N I | CO r>5 H 0 0 A in - N in A N in C O N I - 'N I N - , (N (Y (o ~ CO N- A- A(dA A 0 O No 0-C A m 0 C) HN I A -I H - I - A- r-I - r H A A~, U [N H (N 0 - (N 0 D 0 C)O (N 0 > - N 0 > - I > (N 0 >1 N C 42- A42G 42) -2 0 42> i- n 0>0 H) - H C N S CO 1 A - N A U C O 42 - 4 m A 0 4 - 0 N A 0 I O 0 - - 0 O ' in I A N I m N I -d N in - N in AQ CO m in 4 - O - N CO - 0 CO A 0 A CO 0 A Ad ' N M 0 1 I H -H N A I N I >1 C- H 0. N 1 O - 1 O CO C O 0 1 CO N -1 O A I - i O 0 - H H d -H' d H'ed H o r d H -ol 1 H -4:" 0 r O 4 m CO CO N - C N A C -1 -1 00 CO Nt A 4 0 O rd N CO - A O O A CO - O H A OI s - (i i ( L | - I N - A - - A CLO - 0 - A - CO A L >0 - n - C - r- (y 4 -1 2> H 0 - (0 1 42 4 -|I - |r -. | -. >1 , o 4 20 1 U - -1 - G4 - - A - - A - M - in N N t - O CO , CO) H , CO CO '-, rO CO C-, O -rI |N G, t G A CO - CO ( CO - C - Cr A- H I OGA -0 - -1 IN - - 1 4 m a - - 1 e r1 r1 r1 6 '0 r-, t>1 cd - CO C) -4 C)[ - CO [U in [U - O - CO a t >1O Z-QI Z- Z O d a o - ri N - rio - r- - -i y O -- O 0Z O N0) , 0 > - N (- L- (3 O 0) O N L WO 2011/015241 PCT/EP2009/060168 295 I I I 0 - - I RD | D 0 H I I -- I 42 42 O O z I OA N 0 Z 0 I I 42 I RD" 4) o -t 0-H n -H >1 -,O>1 L L LO LO r 4 (d - m N( N( 04.- 4) 0 4 ..C0- - rd >S I 0 - H ) -H H H H H 42 42 m 4 0 S 4 S I I | | C 4, H -t md (dt (0 0 I O ~, 0 I 0 0. 0. - 0 N 0, N O1 H 0 0 0 0 m 0 0-0 OH- t 0 t - i - 0 t t I I 42 > | 42 I > I H > -H I I I 1 I I LN (0 | 2 rd 0| H 42 cN -- (N 5 H 42 (N H 42 cN cN I ( rd 4 m 0 -- rd I I r d 4- rd I -- (\ I - H C O H - I -' H C '-, I '-, I ' - I H - I (d - I H N H H N H H N H H 4)H Z >1N (N--- H H t ), I ' >S H '~ >1 H t~ Si 4C H - H H H I 0 I 0 0 I 0 I I 0 I H 42-- I >1 1 0 tl (N N D (N 0 t (N 0 t (N >1 4) (N 4 42 M 4) N I I 0 I N I I N I I 42 5 H 0 4 H- 0 0 rd 0 -- Cd 0 0 d 0 0 (d U uu _-+ - 2 A-H ( -H W m H A N - - ( - ) 42 4) Cd -)4P 4 I - 4) 42 4-) 42 >1 c Cq Ts N O4) ml H a) =O q) H l l C I c ( 0 r-0 0 # sO O s0 4-RD0 - t~ I (N't (N m't I (NtO I (N ' 't 4 H Cd H (d ( H rd H r (d ( H rd ( H Cd I 0. 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I - CI - 42 H-1 C) 42 H C 42 H C 42 H CN 0 H >-I [s r C -I H > (042 d 4) - (d 42 - rd 42 - rd H H S - N d N 00 0 N S 0 N ) 0 N 4 0 N l , I x rd ,- 0 r -1 rd -H H I x r-1 rd x r-1 rd 1 42 m40 0 0 d iI 0 5H 0 5H m I 42 - .a 42 - .H -H - .H -t - -H - H - H -H LO( 4)X (N 0 4 N 0 N 0 N 0 N 0 t ( 0 i Il O: M 1l '~0 m1 l I e E ~ k O o E S -4 S -42 I -4 ( N -42 I -42 I -42 I -H (N r H N 0(N o rd H- o 0 (N o r N o r --U 0 I Nt 1 N H - N - - N r-1 N r-1 N 0 | ~, 0 0 0 0 - [ 0 [ - 0 - [> 0 - [ 0 0 N N N N [ - N | o N [ - N [ - N -r -1 0 -1 O 0 I O 0 00 0 I O 0 I (1 0 D - H - -H 4 - 1 0l - 4 0 - ) 0 - Cdl I - 0 - ' - 0 - 0 - S 0 -, (N 0 I (N 0 N (N H- (N (N 0 (N N 0 N (N 0 O H r-I 0 ( H H | H 4 l-1 I H - rH H | -Q I 0 >1 - O - 1 - - I -- - '- -- o - '- -, - d 0 0 [> 0 - [> I H- [ -H- (N H [> | H- [> | H- [> I 0. - | LO - | 0 -4 -- 0 - - 0 - t I 0 L(N 0 LN | H- -, ,2 H- 4 0 42, H- - ,2 H- -r- -, ,2 - 1 '- H - - 01 '- (0 01 - 4- - '- - 1 0i '- N H o - -I - d rG C- (N rd -d Cd r- C ( r I - -, C -- S), O N C) C) -- H- C C) (N C) C) (N C) C o H I 0 42 I H H | H -H 0 H H 4) H H- | CO Cd S>- - H C( 4 r-1 S1 -1 1 > -1 1 -1 S H ) -1 H >1 0 -- 1 4) - 0 - 0 H 0 - \ 0 - rk N 0 - H- .- cN H- (N H- .H- cN .H- H- *- cN H- .H- cN -- H- .H- cN H - t - - r-H O '-- -- C H- 'O '-- ' - r -oH 0 Z > 0 - -H 0 H oC -H 0 - -H 0 >1 - -H 0 U H- O n Hr- 42 H- m) H- - r c H -1 (C H- H- 42 (O - Hr H- S1O H- 42 0 cN 0 0 0 - 0 0 cN 0 0 4 (N 0 0 H N OT >1 C (d >1 > >1 >1 >1 >1 U >1 > >1 >1 5 N Z-r Z-r z-= 0 z-r 0 o O 0 0 0/ \ -Z/ \ zO N O N O 0N N WO 2011/015241 PCT/EP2009/060168 296 x 0 A d 2< 0 H 0 >- v--Id v-- .1 (H -4 0l 0H 0 I4-) 1 09 0 0 I 0 40 -H d (H -C -0 0 0 -I 4-) (d 0l U 0 o1 Td >v q - 4 -) 44 u (H t CO AC r wt Q H C 42 C -Q (H U , -d 4 4-) 0 () 0 (0 m~ (H u t 0) 0<0 I 4 v-I (2 u- I p 4 0 >HC 4- 4-) 4 - Cd (N P4 4 - H 4-) 4- Cd v-H -H $ad v-H bI >1 v- 0 vH 0v-v v >vv- >1 0 Cd -Ci0 N I > Nv- dC OD (d 0 (0d44 HC I .Cd - Cd (N IP 0' - n N 2 - N N (N Fi v- 0 Fi- N ' 0 -Q *H Q FD (H (N ri - X 0 (N M C N I'- CD q (H -v 01 r- 0v-) 42> . 0> 0" 0 4- D r- - v(d 4-) v-x4L 09 - O C 0 0 0D (H CD 0T Z) SH Z o= (H 00 WO 2011/015241 PCT/EP2009/060168 297 -P c- O LO 0 oD 0 00 0 0 0 0 (D 4 4 (d 0 A~ N Ar -n A:m - q4 a4 C14 a4 a) -0 -0 a) uI A .1i 0(D a))a Pi 0 N HH 0 0 4P4- 4-a) 0 0 C) 0) HN r.I (N r. AD0 D ) 0)A 01 4 4 4 4 4-) 4JH c E cc H- z-1 0 00 .I, N HH N 0o, -80 0 0z 0 H- r Cf 0 HHHHHH z WO 2011/015241 PCT/EP2009/060168 298 (I (N cn (Nl (NI (N oI 00 7t -0 -0 0 0 0 0 0 0 I- -I- -P~ 0 0~ If)) LO LO 9n -) U-O 4.) 093 0P U-) 0-) -H 0909vH p09-Y - I- N -) Q0 U) 0 1-- N9 -l LO Q0 4 0l Q0) N9 0 LN -4 0 En 00 00 o0 0 0 0 0 0 09) 09 09vH ~0-0 I 44 ) 0 ~ 0- 0 N 0 0) 09 m9 09 09M u zi Z-1 Z- Z. 0-4 09( 9 9 o ~ ~~Q C) C ) C ) M ci) > o 00 (n 0 (N Z- 0 0-I ,r z~ ~ WO 2011/015241 PCT/EP2009/060168 299 | | O r-0 OD o -H GD 0 I I 4-1> H o 4j9 NaN 4-H I r- -r coo -o tO O GD 4 Q4 .5 I + 1 n Vo V1 N H Cz z - a) r O tL -- --- 4 y u II H O 0 r GD GD D .-. 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'- H| C to o o o o o 0 0 0 X 00 LO X, 0 0 ) 0 N 0 0 0 H H H H H N N x M N N WO 2011/015241 PCT/EP2009/060168 308 I II 0 I0 0 0 1C 0 N0 1 -0 I 0O I t I t- I o -H 0 >1 - >1 - >1 (C N 0 I -|4A 4-| S o O r > r >1 rd - I 0 0 C V 4 O 4 C V .- I I1 1 (Nu - u A V V V t 4 U V 4 A A A) C] t 5 ) -t S Vr -,IH "o '- H 0 ' -o 0 -0 -l>10 4 V - V ' - m rI ( 4C 0 N d -- Nl H l (d A I - I 4 I 4P -A A 4P x H 4P x >1 P N - A 0 I V 0 >1 V 0 a V 0 - (N A (N >1 (N -H Nl A I Nl C I Nl I I Nl ' >1 ' 0 ' t >1 >1 Vd V0 I (o (0 A Vd Vd 1 0 4 0 V -H H 0 40 C A 0 C 0 C A 0 4 0 4 0 CO I (N I0 (N I t( >1 Al VS 0 A AZ V -( t N 0 4 N S N I N C0 -- 0 A 0 0 A A 0 A 4 - rd 0 0 N I A N I I (N V N N N I N I 0 0 - V I - V Z - V S>1W 4 >1 V >1 V N V A 0 0 Z 0 0 A 0 0 t 1 - O I A A I A >1>1 V C) - - C I - C I Z 0 HAZ S -- S 4A 04H0 V I C O V N MO V O m -0 V 0o V 4 m >1 A N At '- H A I N> 0 I ( I I C V C) .4 - V0 -- V r I - V0 - 0 0 - 0 0 Z 0 0 -- V 0 4 (N 4 I (N 4 Z N 0o 4 Z N 4 I N A tH '- A 0 N A 0 | n 0 I 't Nl t Nl 0 't Ni >10 Nd Sl - V I - V 0 - V A-, C> r 4 (d 04 rdCO 4 d - A 0 N A 0 n H 0 1 >1 0 0 1 -H rd I I V I -- - A 0 - A - H 4 C (N 0 C N N u N H 4 (N I 0 C) 0 C) H 0 C 4 OnH A V A 4 V A I H (N A >1 A A >1 4-4 H >1 V t3 C-] t I I t I t V I C)- O C - C) I C)O - (0 V 4 r 0 0 r V005 I 0 V I 0 rd 0 0 I V U A N 0 N 0 A N 0 - (N 0 Z - N 0 - N A - N >1 4 H HA 4 H 4 H I -H 1 0 V(0H I 0 (0 p 4 I C V C) > V C) Z 0 C -- - -r- I - -rA - - -r D O 4 0 , V - 4 V A N V A > N , N l H N A -- (L md ) I rD Vd I 0 d 4 0 ( >10 V r 4 0 (V 00 4 0 4 A| 0 4 (N A- 4 V - > - C V - ( -t (N 0 4 0 >1 N' 0 -- 0 C)O CO 0 4 CO 0 OCM 0 0 - V V - V 4 - V I C O V d V N V - N rd - N -S-1O CZ-- 0 4 0 D - H A -- c -- ! ( 0 -- D ( 0 r N 0 0 N 0 V (N 0 - 0 0 - 0 - V 0 - V Z -n 0 -A H4 - 0 N 0 A 4 0 A 4 H 4 A 0 C A 0 C A 0 C N A C A I -, I - A I -- AH >0 A H >1t H >0 - >1 0 (N 2 0 N 1 0 N I - C ( - C I - C 0 r-A C ( Ar- VrdI Ar Vd C A ( CO H m , CO m H H r H 0 H 0 H 0 A N >1 i N A A N 4- N >1 -H [> >1 - [0 >1 -H [N -m 4 i ( ( - -d I 0 -d 4 N -4 Nl - 4 ZN 4 (N -A O N -A 0 0 4 40-1 4-) 4W I A- N V rA I A- N A - N I - V I - V I S - r - 4 d i - d I 0 r - -A S A S- A 0 A - 0 A >1o -0 -- T -- , - 0 - 0- - 0 0 - 0 4 - 0 - o C) - o U -> C A 0 N 0 N A 0 N V [] N - | | I I | C-1 A- 0 (N A-1 C4-1 A- 0 C ) - 0 (N to A- (N 0o A- 0o A | - V ' - V I | - V 0 0 V '- I - '-' I - '-' I 0) 0> 4 0> 4 0 0 4 I 4 I A (N I A N I n N A r, A, r-(-, N CO r N >1 '- Z >1 '-' N >1 '-' I o N 0 (N I 0 N I - N I 4 0 I 4 0 I C 0 - - - A- A -(Nm -~ 40 - 4 0 -~ 4 0 -- 0- - -- 0- - -- r - - U - - ) -- > V A -- A U V A d - [- (V - [- Vd - [- Vd Ar- V( 5 N Vd 5 N Vd 0 N 0 0 -0 0 - 0 0 -0 I - 0 -r (d 0 A - (d 1N - 0 N - 0 N - 0 N 0 (N t N (N ' N N 0 Nl - O - - C - - O - - ( - - I >1 - I >1 - I >1 U) - H U - A- CO A r- 0 o U C O (Y 4 CO 0o (N (N '-- (N (N '-' N (N '-' N -r- '-- (N A- I | (N A- I | N A- - Ar- - Ar- - A, N- A r -1 Z A -1 Z A -1 Z A CU - A C -- A C - C - 0 - o o -- o Z-Zr ZI: LO / \ -z 'zr /\ -zz/\ ' O O O z x N N N NO WO 2011/015241 PCT/EP2009/060168 309 0 (N I t I I - >1 0 (N - d m 0 I 4 U C >1 d C >i t- X H - rd CD ' I U A ( o m Y Cd t >1 Cd 0 >1 N - -H A I ' I Cd 0 M toD C I rd rd 0 4l 4 4 |d 4- 4 I I ( I 0 N A 0 C A 1d rd 0 (N 0 >1 - o O00 U a t- .. tO 0. '-t ( I - >1 q- 4 N O C -0 N4 d Cd - A A O H- - Cd U - 0 U I N I 2 U I 1 >1 0. - Cd 1 C 0N C - U A 0 C 0 t A -A 0 rd AN 4-)dI S I - U 0 (- C rd 0 rd m 0 d V C - - +C A ' H O -H >1 A -1 I - rd -M V Ut. -4 Z ( V I | Cd V A rd I A- C GD Cdt'- C A- N -, - Cd aO Cd S - 0 O A A G I V -H 0 N >1A 0- - C 't A- C W V H HO d -- -C Cd 0 U >10N 0. I 04..Q U A >1 \ -0 1 - 4- Cd 4- UU0A ~ - G C) rd > Cd d -1 U- o O >1 rd 00 U I| 1 - rd OA 0 I - - C A- rd 0 0 I- - - N A - H H I '4 N 0 > A 0 rd rd A - V - A 0 - N H - (-1 0 N ' t-0 0 >1 A V U - r C - N .C d d r-A U -- 0 C V - N I I t I - 1 0 0 0 0 CA C O - A C A- N C N - C A I r- - - Cd A 00cY1 -- Oc cal co Z 1 ' 0t - 0 (0G C -) U I N r-I - - 4.. rd -1 0 0 0 - I o r- A V CC A - ( N - >1 1I -H I (- - ' A 0 N C 0 V 0 I - V A rd | | - 0. 0 0 C - (-1 0 O n I - - 0 > 0 - - >1 - - tOo | CC> U 40 A - I0 A - I Cd - '-' I A GD 4-1 to a U A-1 , c0 >1 1 I I - Cd U '-4 0 GD A 0 I 0 I I V (N-1 I 4 0 I 0 - I Cd >1 Cd( V - C -'10 '- A t- t rd S N rd V 0 Cd V U 5 0 - rd 0 | C I o rd - | >1 - A N - I A d 0 00 04 0 - rd 0 - - . A- - vr-1 - >1 r-A - Cd rd // - -z -z 0 //\0-z rI WO 2011/015241 PCT/EP2009/060168 310 V
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II 0 Y Cd) CV-4l 0 \ - -Z __ _ z WO 2011/015241 PCT/EP2009/060168 313 0 I (4 o I -- , I I I 't H N I 0 H I 0 N r- >1 o Z a) >Z a H r-I A 0 I 0 0 0 C 0 I >1 rd - H H 0 2 -H O 0 D -H 4 a t I ( 4- O 4 - Q O 41 M O '4 I N rd 42 N N (d 42 I -I t *-r H ( 't M I rtH I (N U - rd S >1 o A > 1>10 U >1>10 -- H N rd t U I tC N A I -, tC N A I I I '0 >14 a)N 2 -H - r d 0 - 1 O rd 0 - A (N Cd rd I 0 a) N H Ut, 03 - U Ut, m3 - '-' 0 42 (N ,Q4 S rd 1 l) N -H a N - N I (N I I N H N Ut'O rd0 -~ St r '-' (N - AH cd rdtI >1 0 0 U I 0 rd 0 U I 0 I 0 O O0 U I ,Q 't I H U t," I H U H (N 0 t (N I (N I t N I - >1 H H I -- >1 H >1 -- U, N I -H Cd Cd 0 tC N >1 Cd 0 ,t N Ct U -H OH s 0 U 00O v- 42 rd tCO A 4 Cd 42 A >1 I C(] I o I rd - N - 0) N 42 (N - - N O) - U 0 - V 1 0 0 - N S >1 0) D I N S >1 q) S m d H- U N U U O I -H 04 t -- I -H 0 0 -H N H At - H (N Cl t~ I H - (N 0 t I H ' - rd I - U >1 >1 A S -0 I 0 S >1 - U I 0 S I N - N I -) tC tD >1 Cd m - ( (d I H ( ( rd I A N - A '- 42 cd N A- U A I N A u H I N A s4 I - rd Ol U 0 -I 4 - - 0 0 I - C4) - 0 0 - A rm N ( 4 -- C) ,Q 0 M I H 0 o 1 0 N I - H ' 0 Cjv 0 Q4 0 U CU I - 0 U -Q 004 HO U P4 A ,U A 0 - A OH 0 42 a0 A H - 44I A >1 0 I a) I - O >d '- - d ) N 0 0 U C) >1(0 NC U C 0 >1 H N U Q0 > - N H (N H 1 HA U A1 4-) H, (NA U >14-) H, A- - C! 1 030 d U -- - C O rd U -H - 0 > a) U O - - H 0 0 N OD co M M I -H ,1 M N M Q H a) r! 03 N C2) - 03 N (N 42 C) -0 A -NA ( H H - O- H I t 1- O I I H (N -, 41 H > O I -0 0- - 1 O | I I 03 H- H wd -1 - n N 0 C ' I m a) T - >1 a) - X | - > U - C) 0a A U r -I N I (\ -H r-| 0- N -I 0 -H 0 r- a) H O 0- r I I [(N Ud I H 0 0 NO - I (N 0 0 0 v-,- 0 - - 1 I N N U - 0 (N N Q - A U a - U At 0 (N Urd- I U H 0 U -- U A 0 U H 0 s >1 H I - A rd 0 a-) >1 > H 0 0 r-A >d >1 H -I r 0 (d 0 U - ,C - U N a) ' O - U ,C N '-' 0 M A - A 1 0 - H (Y) m I 0 m -1 ( C H 42 r A 0 - H A N 'N H( > A N (0 H (NO N >1 I H >1 H- 4-- O AI - C! O - O A N A I - CU t 0 N t - - I 0 H 4 ) - 42 H I 42 - ( H 42 A M 42 4- 0 0 A N '-' I C-H q) A N I C H A a- N H I -, A -1 4 0 -S 4-) zl0 0 -2 r,03 >1 So A I 0 >1 - O- -1 >1 --I O -- I (-d> -- I H -- OA ca O a (- - - d A 0 - - a rt ( r t - >1 0 cq(ND3 -- 0 (N 0) A1 U - 0 I 0E 0) U 42 N - - N I r N - - \ ' -- O - N | > - [ -I a) r- I U -, - rd r- I U | - dCU) - 0 - I - 0 0 -r- H I I 03 H I (0 03 -r- I - rd I H ( I rd rd >-1 0r- r- rd rd -1 A HL r- rd -- 0 0 (N- -1 '- ' (-I ( N t - '-0 3 N t - O r- (N I U I D 1 0 1 A A 4 H --- - H AC 42 m -C A -- - - o U (N - >10 '-' | - - a) '-' r- - -N o q) . | [ C 2 S r C] - 42 S 0 - r- C(0 O U C4] 0 N- OH - Us H 0 '- 0 - Ux I U 0 0 0- >1 Ol Cd 0 vI C d 0 , r -I H r- C I V C 3Q r-I H a) z - Q | O E H mC)l I 0 T 42 0 q - ( -04 t-vI( -0(N tc -0 a) N tC N (N 0 r,I N 1 N - ( - 2 0 - 1] >1 - ] A 42 (N CC) -C -4 AQ 42 (N 0,-A~ ~ ( 04 0 0 N4 A- N N N A o CN] N N I C \] N 42 N N - O ( -I r-1 >- N , - r- -I (D C , - -1 -- J W ZC ' -- 1 O --1 Cs] a) -- >1 A - Cl -- >1 A - A > 0 Cl d A - r A N U 42 >1 A- U 423 >1 A- - U 42 U -1 (0 4 Z zI z Zz o / / - -/ /1 1cr \ / C 0. O O OV) CV 03 Ct 0 0 H- H- H- H- H- H- H z WO 2011/015241 PCT/EP2009/060168 314 V 0 oPo oo oo 00 (D(I
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N> c z WO 2011/015241 PCT/EP2009/060168 322 t 1 01-( O 0 -ON I O 44 0 I N ONNH ( H'--d - C -H 0 a 0 0 0 (- 0 0 1 0 O4 N l - ( 0 t r-I q) I -1 0 O U) 4 O 'O I 0d a -- 42 ( -42 tO- H a 0. . -r- - )-]t O H 42 4 O q -H ( S I -H I 0 4 -H 0 I a) a) r ) 5 W 0 a H U S tU ra a )o 5 -H 0 a) 4 I rd I ( t >1 H r H H 4- d a) 5 i t H- 1 m d N 3 t A 2 I -- 1 u 5 I N ) '-0 >1 r C 0 o H >1 5 42 0 H 0 -Hi ) a0) -- >1 r 0 0 IQ -, ra , ( >1 k 0 04 Q >1 a - H N e-1 0) ( d X 0, "0 N 4 c z- cxMO rd N " -- n - rdO a) O c t 42 t OH N r 0 a) Ot -- i >0 a) - a) >1 ,2 >1,o 1,- a) 0 ,0 0 | H O N - I I t (N I a S ra 0 ]) N I 42 t ( >1 I 0 ON - a) rd N C H 04Q 0 - N M a) a 0 - rd H - (N C -- q >1 O 0 a) O H a (i C I H H- - - I >142 I I t 42 't N - H I 0.42 I 0 >1 H N ) ,2 a) N ) a) a) 42 a) O Hr- - ) a)-- N N I >1 H- 0 4 4 H- I LI 42 (1 I I>1 C C I 4 H- I H N 42 - A ( I A 4 A 0.4 0 42 H A N I I I 4 N I q a) ) >1 - H $a 4) 1 42 H N I a) N 0 42H -1) n 0 04242 r a) 04 42, N o) O00 0 OH I 0 -t a>1 A 4 I N I I 0 Q IH t N NA N o r H-1 a) ,2 - - a a) O N a) 0 a) a 0 r )r O H -1 C H N 4 0 1 0 0 A 0 H N A 0 0 A H S | - C C -Nt N l' N S | H ) r- ( N -t (Nl a) Na 04,2 0 - a) t- - rd ,- - a) r N -4 42 - rda) . N - - O 0 N I 0 0 I 0 - - 0 I 0 N I r q - H C H 0 N N I N N H | - r| 0 H ) 0 | 42 N 0 C I 4 HC-I - 1 N Hr- >1 N - C) r-I 4 O3 O ' - >1 N N 0 - 0 - I -- ' I C 0 >1 - N 0 - U -1 0 o -1 o 1 -1 - m -- 1 -1 0 o O c - a I - v I - o >1 - I I 0 o a) - - 1 - 0- >1 N>[ N N N >1 0 m 0 ON - N LON 1 L D 0 I - rd I - C) (N r A 4 - A | [ a) I -- I O I I H ad H OH H a 0 - 0 u C H A H a) HO N >1 - ( >1 -I N ON a) SN >1\0 ] >1 H- N >1 ) 4 Lo2 42 H- a ) H H - A 0 42 4 42 H Lo A- V - a) 42 - -- 4-A - rd - ) 42 LO d - A -r (l 0 N N 0)0 (l I A N I A N 0) - N 00 (l a N 4J 0 - PH 42 OH a) N H mCN 0 5 H- 42 5 a) - C N -- - a) - 1 2 - 42 A-- - N -r- - -a) C N 0 I 0 U) 0 N I 0 0 -0 0 t0 C 0 t 0 N tO I O I 0 0 I - 0 - -1 H 0 -1 H I I q) - 0 I -, N N N 42 N 0 N 0 - u I - 0 N -42 m 0 N m 0 0 H 0 - - 00 >1 0 0 >1 H - -OH 0 a) - - N - [ 0 A- - 0 (N - C - >1 N - [ 0) - -A-1 42 0 i r 4 So 0 O o d o0 042 H 0 1 4Q 0 5 r) 4 - I 0 r ) - N 0 - N I - - I 0 I r) N I 0 0 - N H> [ H> [ 0 ) 0 0 - N 0 - 0 (D 0 - -l 0 r >1 -r 1-N - -| (N 5 - N r 0 L| r 0 0 H 0 - -4 20 41 I 0 (N O 0 - - 0 >1 0j m oz) -N a - 420 I 0P >1 - O 0 - 4 -- 1- O n - - O L) rd H- O 0 r- H r-H r -| - r- 0 r42 I -, I - N 0 - N I ' I I - I a) H- 0 I 0 0 -- rI - N X N 0-H C) - H 0 CQ) in -I ONv 0 ON N 0a)N 0 H (N I Q H H H -- N - -' c N C r d M a N -1 1 1 -1 7 -1 - I - - I 0 - I I a 0 I C I >1 r I >1 I >1 0-- >1 -, - -04 O 2 N 0 - 0a - -- -0 I H U 42 N U 5 I U) N - - N -,U) I N U) 4 1 U) -H r- >1 d 0 '- d a) - a) O 3 O - 0 -1 rd 0t - 0 0 0 I D 0 -- i - c -5H 0- O - 0 0 5 I 0 -r N -H N 5 H N >1 N N (N - H (N - N I - N H N N H ' - - 0 - 0 '-- 0 -420 - CO O - >1 - - 0 O - H ) >1 (1 M1] 0 I I - C I - 1 I (N rU 0 0 U) (N H-I N 2 (N ( ) H N 0 0 N 0 N 0 (l N -5H N (Nl O O 42 >1 42 0 H H - - H - H N >1 -1 0 H >1 (N (N -4 0l - 0 ( - - H - - H - 0 Q -H A ( - Q (N (1 U 0 I O) a) (1 0) ' U) ' ' -rI I U C1 C1 U I >1 >1N a) ZN $a >1N -- I --N (N UI N >1 >1N -I 0 -- - O --- L-O 0 L C 42 H - -Pa - , I-L , 1-L , :-L 0 /o \v \ z z bz zz olI 0 I= Ol o) CY) itL k - mo( Lo Lo LA Lo Lo Lo Lo z WO 2011/015241 PCT/EP2009/060168 323 0 I 0 I C) (N C I -42C I ,C N9 I 0 H (N C) I C) I I (U - ( (0 t H t (N C) N (0 >i mU 1 I0 t 0 0) .- W C LO > - -P -P 7 " -H I - C2 C U -H U (U 5d C-) q) uo4 2 5 5 4 rd 0 ( O I (r H I rd o - (C HO 0 C 0 ,m 0 0 N rU I - (N ,Q -H N ,Q C - N U ) T N U C l t u S ( - 42 I 4-) M 0 (U - 0 (U rd ) '-- i C | -- - O r r1 O r C) - 0 0 H- ( I 2 (N C C- (N C I H - H- -- ' (N I - i > - I (N (N I I I > -- 0 N D9 (N r-I Hr-I M 9 (N (U '- n- H- H- I H - H | H- C) H- 0 H- >9 - I 0 - | ( 0 - (d I (N > ,2 (N ( (-- (U r N N N 0 I 4 H- 0 I H 0 -H OH -1 (d No N ( - A 2 - A C -H -H 0 N I u N I N O ( C H- C- -H - 0 H r U O H- (U S4 H-1 4 -1 -H > -t N -t rd I) 4- -- d x .- Oi ,C ri r-1 rx N 00O N I - ( 4 H- N H 1 N 0 r-H r-H 0 0 o t 42 - ( 1 - ( ,C - -N H- (-1 rd 904, 42042 O o 0 0 - - N d H 0 I H 0 HU 9 - H H H C) - H - - H u. O -1 [ r- 1 -1 - -- o0 rd >I u - - - d a a r 0.4 N -C 0 - >i - >i >9 [- N LO [' N MU 42 CO 420 C) I - (U I U D rd t - H , - H ' ( U - rd - (N L - I - r H -H H -H N- H s C) (N ( N ai* (N N i (N N 0 -H I - N-r , L t 0 U 0 > A -- 0 - - rd I - rd N 0N '-'O -N (N 042 1 02 O 0 '-, I 4 0 -1 0 H O (N ) 4 C C - d -H N - H (N H C C- C (U -A N '- O H 0 5 H 0 CC)0 LH - -(U 0 >o 0 >9 0o 0 01 I -0 - , 0 ,H H 4 (U 0 > - O A H H 0 H r- I 42 - I L 0 0 H (U r- (U ( - , '- O$ O 0 - r-I $a I - C) 0) -) H 2 42 H4 0 0 0 C) 0 1 - ( H O 0 0 m) ,Q o -i o H C I H 0 r 0H (U U r- I ( H I r H - N 42 C) 0 0D 0)C ( - 4 2 a- I (N H I 5 n l H -I M1 -H ( > (U >(d - >9 o '-0 m >O 9 ( >9 O' (N 5 4 M r 0 - - 0 (0 0-- 04 0 0, --, r 1 C) O H t r -t 0 t 0 C) d 0- (U 0 rn 5 '-- 0d H 5- C) r-1 5 N) (N 5 t- 5 > H H -5- (n H) N) (n C-) Hr-t (USm C] -H Ct H >9- H>9]H H9> O9 - . C) (U r- ') '-- .5 - 'O O9 - >9 O9 I- C 42 - - r- O) C C rn - i -1 In -r I >9 | > (U H- I >9i > 9 0l >9 (N] 0>9 H- 09 42>9#>9 >9>9>93 - H- - - H 0 LOl C~ 00 o o CC b o o o o z N O i el el ril L2 WO 2011/015241 PCT/EP2009/060168 324 do ~ o ~ ~ o do o6 H 00 0 0 w 00 u ~ 0 0 ra0 0 ~ (2 0 A r -.u C) H 0 04 C1 T C F-4 F4 4 F-I d r -) u a - 0 -0 u 0 q0 a ) r Q 0 _ci 0 d -1-- 1 04.) 10 0 0 t 00 0 t d N0 ) o . 0 OL LO M MO Q Q d C 4J CC 0Q zz zz zz , u >=o )-=o oc o oO o o 01 C r o sC r-1 a4 -H 'z 'Z zz rz= ra, 09 a9 _ . N a) Mn M M. a) 0 1I ccz90 WO 2011/015241 PCT/EP2009/060168 325 UI) -P . 4) V Lr01 1 a 0 0 CL CL 4a A 4 i 0 0 0 0
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4 u u -P I 4-) > ) >1 r , Hi 0 0 Oi H -0 () H 0 P4 04 Q) r- M 4W m 0 z z w >1I a) 0 4) W 4-)-H 4 caNCJ ' \ ZZI 0z z =Z IZ =z =z =Z (N0 0 0 0 C\J cfl -0 0 0 z WO 2011/015241 PCT/EP2009/060168 326 u u * 00 0D4(0a 4-44- -P H- H H 40 oc u Q u 0 -P HU a P ( m mo o ~0 0 0 a) 0~a ~ a P4 4-3H ca) '0 0 0 O C 0 u) U) m~ L rd ( c H C v 00 z E0 U)P HO (D (U ~ (N v- WO 2011/015241 PCT/EP2009/060168 327 In 009 z 0 0 0 0 0 0 o w 24 24 24 0 c) I-- -oI -P 09 09 09 0) a) CD ~cJ - C'J 0 9 GD LO7,V L)L vv00 0 0 0 0 0 0 oo co0 c 0 Q) 0 > 0 Q) 00 x4 04 H 0 a) 0 L z WO 2011/015241 PCT/EP2009/060168 328 ,I P 0 0 0 0 0 0t 0 D + ~ - N( N(N ( 0 C)(N(N- (n 4J 0-) (N ( (N7( C'J CN (N 0(N ON(N( P4 0 0 z 0000 0 0 (N (N G)) ) zm zj 00 T2 I~Z 12z = cl 0 0 - 0 -- 0 -- 0 04 H 8 C7) z r~1 m - 1 WO 2011/015241 PCT/EP2009/060168 329 mn 0 oDa C) c) 4r) 44J -1 -r-i e -i C c HH -r - m O0 1 0 - 0 r H 0 CQ H E-1~~'- Eq ( CeN I 0 (N - H 0 O CJ 0 Ce Ce u 1 C 0C Ln LO4- H H, -z- - (U HY H e -) C) C)q 4-~ ) LLO U Lo Z= sa ZY 4 z li~-- C e U 0l H) Ce P4 I Z- Ce OH 0 04 o-1 Ce OC WO 2011/015241 PCT/EP2009/060168 330 |3 1 ii O ) I -H d| O xN, I Oo -, r C ~ S -10 -H C - -H .H r) - 0 411 I H 4 ri o S , d rd ) - rd - ' , | 0 H H 4 H 4 0 H'0 d0 Cd - >1 _ , r 03 I u r- I >1 Cd H 4 r C Cd C , (9 S 0 Crd 4 Cd~~~- Cd4 Cd>1 9 d C 1 - l H >1 - d H I 4 0 H1 0 0 -Ha I >1 H ) r S O S C I ( -H I O I N I I I H1 , r, 1 O M 1 1 H m , rd >1 rd> H H >10 0 0 - C I I $a 4 dO - 0 0 (N I I r - 1 >1 1 HI I r - H I I > v-O 0 C H 0 H -I >0 0 > - 1 -- (N H O H9 H o- H Hd 0 1 O I) O >1 C o1 I H H 0 4- - = 0 (N X I H N -H H -H CO -H >vd H CE H Ir -H CO -r O 0l qo l 0- l >1 H >1 >1 H H l O Il -r- I 0 I I (. 4-) - H 4 01 I | I I 0 | C- 0 I 0 r-I H r ' I H 0 I I N H 0 H N H H v-, I H N- -- , r H O H 0 r-1 l N 0 - | -- (N '- - H r 0 H 4 0 4 I0 a) 400 .14 I 4 ' I IO - I 4 r-I ro - r-I 0 I '- I . rI - I - I - 4 - I ' 0 - 0 > 0 H 03 00 rd 0 H r | H 0 H H - I - - N - - d 0 0 1I I 03-' - N - 0 0 0- r - 0 C O '-- 0 -1 0 r >1 rd '003d 0- 3 Id C '0 C O C I 03 0-03r o u I O >1 u 1 O0 - H O, - H U >1 u -- v I v in v-C (I 0 v- C ( 0 v iC v 0 - > ' - - > ' 0 0 - I ' 'o Ocd v- C -C 03 v- '0 v-C 0 0 '0 0 -C r I 0H 0 0 1 0 o) 0 03 0 0 0 O H O CO ( 9F19 I 0 (9 >1(9 0 C 4 C m C 4 4 v- 0 - 03 C C rd r, I , H r, I M | rr , H e H 0 rd) 0 I 0 aY) - d CY) rI - - r- 0 I 0 o 5- 0 O 0 5- m 5- 03> m > CO 0 I CD I -D ID I DO vC I O I -" -30 I ." -- CO H H) I .W O . -C - 0d - iO '-- in-- >1'-- o - rd I 0 I 0 0 II 441 0 H H O H 4 O 4 H I CO v- O H 5 H CO H- O (9- rr) H- rr) H 5 H o r 0 >1 Q0 0 >1 I r - ~ ~ ~V '-- U '-- -- -' d -- U - - -' rn CO rn O rI O rn -H m (9 0n - In O rI O - -I 0 - H O I O 0 -- O C- CO - C O -- (9 CO -- H ( H- O H- C -- >1 03 >1 I >1 m3rd I >1 I >1 | O 0 | 0 CO2 0 | H |O N C2 H C2 0 CO 0 - OH O0 - m 0 d O H o l Li 4 I -rie1 4i - I r- (9- v-C (9 r ' r- H '- v-n 9 r - ( >1 -r >1 |1 (0 '0 >1 o- o( N N N N '-- N N c N I '-- r -- N '-- N 0 rd 0 C d '-' Cd 0 v-1 C rd in- r- -- d '- Cd S -H l -H I -H (1 - d N I - I -H I H 40'- 4 '0 O 403 40O 00o C t C ' rz zz )o >=O >== >== OO O n ol L) 0 0 CD 0 n N U) M N M Mt 0 M N z WO 2011/015241 PCT/EP2009/060168 331 (D 0 0 H I I I S d 0 0 x O T 0 0 Cd I o9 O91 O 09] II rd I Cd rd 09] -1 O O O V -H] 0] c C I 4& 5 | 1 - H T ODc C N Cd I C - (0 0 rd 0- 1 O O r )C I C >1 (NH I -H I H I I 0 I V I '~0 '0 r >1 r-I r- s - 09 -- | I - V v-| -- 19- vH I I 0d >1 | 09 I Cd ), -H 09 -H 0x9 19 c0 | 0 c I - I D I Cd 0 I Cd I r- 09 o0 09 r - r r- N r- >11 |I vH I vH vH I I H 0 H C C - >1 - >1 >11 09 >v I >v *r- Cd O I O I C C r-| | c0] | '~0 *H- C 0 C 0 *r- *H 09o I 9 *H 19 *H r- *H -H '-0 1 09 I 0 I vH V S 1 S 1 *H 4J I C C C 0 I Cd C Cd C r- I Cd d 0 d 19i Cd-- oC-- 0 >o o 19 '0 1 >1 - >119 >11 19M I I V 0 L >10L o| 09s I 0 9 - v- 0 v- -H v H v- vH v- - >1 v- >1 v- e0l9 S '-0 - >1 - -H- ,V V , - H -~ - .. - | | d -- ,d -, - I D I 03 0 0 O Cd IC I I I Id Cd v -H Cd- Cd 0 0 C-' 09 C-- 0 C I> 19 I 19 * 0d | | | 9 |* 0d H Cd - Cd '0 C cI Cd cI Cd 0 C V1 0 1 I- 09 '-- 0 '-- 0 C Cd -- , Cd -0 '| Cd |- Cd' S C *H C r-1 - -'C -- 'C r-1 i 0 S 0 -0 I 0 I 0 -0O 09 C Cd C - 09 C4 0C C 0 r- , r-| I M , I r | ' 1 V .0 V Cd r- V 0 -Hd- 5 - - O o S - o S OC I 09 r I 09 I 0 C I 09 0 I 0 C 0 O 9 V 09 - 9 v- '-0 0 - d 0 - '-0 09 vH Cd v- 0 C d v- 09 v- 19 -H v- 09 C v- 09 *H v- 19 C I v- 19 I v- I >1 5 I v- Cd I v- S >1 Cd - r - 19 (r -- , - -- - Cd -- 1 0 9 O0-- 09 0 9 -H V 09 0 0 0 0 V 9 -H 0 O9 v- r- 9 v- 09 I C 09 v- HI 09 v- d O9 I I 4-1 -0 > r -1 O - 1 " OO -1 O O r - >11 - >1 - Cd rd - > -- , - >, Cd - Cd r92 19 -H r2 19 r0 N -- 09 1 v- 0 1 -- 09 N v 0 *-r- '0 09 -r- D9 Cd r- 9 -r- >1 0 -- v- 09 Cd )1 - 1 - - 1 - -r- >1 - 1 C - 1 >1 -]- C 0H V 9V 0 00 9V- 9 9' Cd 0 1 Cd W I V r 0 Cd V 1 I '-0 -- N l1v- - N 0- 9 09,C - N -rI '- N V. 0-- -r Cd ( 1 L '-' Cd '--' v- '-' Cd LH '-' Cd . '-' v- 1 9L 1 -H >1 1 -H I rd 1 -H >1 1 -H Cd I >1 z Z Z 41 0) 0 00 0 0 m / \ /\ / \/ \ M. U r- oU O0 H 4 CD - D - )z ) C 1 1 ) - D C 4 u >1 u 4- u x1 - 1 u") u " u u)m WO 2011/015241 PCT/EP2009/060168 332 0 0 -H N Nt I I| C ot o l01 -H H -H rd 0 IO (NA I H IH >1 1 d I C 00 (do -rI > 1 -rI> 10 r- I Ht I q I o e- o e- 4 p4 - H O -HO H 03 - 03 - b |) O O O a 0 -r- 4- 4-)M I H I H 0 N H1 0 C) 0 C) i I C I H zO too 0 CDC' o 11 o -- o I -4 ICC H- HY 4-P c0 (D 1E-1(D 1(d v 0 (D01 0H - U C) H tD C) n- LO H o-- 4- ~ ) U) -- 1 H- D (d Il 4P) 03X H ~ U 4N 00H 4 ( Ic -1 0~ IQ2 ) HO O b 0~ Q)N Z=3 ZOO r-, 4 l 4 NN 0 a) 0 O z z Fid Ldi WO 2011/015241 PCT/EP2009/060168 333 .H 0 0C9 u9 I' 09 I (D] 4) A 9 090 0 09 0 I)i -4 44 -P -1 0 (1)6 0 $4 CD (D (D 0 09 0) (D P4 0 Q 04 0) 0. 4 04 -0 I m 4(1) 4J 4-) H HD m- (D u a) a 0 a u 00:71 0 m 0 -H 0' -0 0', rd H H U (D H1 (D >10 - >1 -0 5a. v-H4- 4-J v-H 0X. 0.( 0m 0 m I $a. (N] (N] (N] 0 01 v-H $aH 4. 4 4) 0.F jF 0 -0 0n LO 'I CDCDCDCD0 c'J pf U )nf m H Wcoa .- P . M Z 0 C 0 0 0 ) 0 00 ac , cc co 0D OD HD HD HD H0H 0 WO 2011/015241 PCT/EP2009/060168 334 0P 0 oPo W ~ do c c- y Lr .H 0 -H V-4 V o C L, PQ a D4 0 H A9 0 4 H00 k a HH o ri - - C (D D . c P Q ( 0 - 0 0 0.10 t H -P > -C(.u(D 0 a) zz z 4 0 p 0P H 0. o 41 1o 4 - (1 2 04 FT4 $a .. u . u. u -- o -o 0 4 F4 r. (d mO m Hr -r OD 0) N )0)O -P p1 m- 0 t t -m =z==z \=\ LO C4 a4 0 -4 0 -&0 3 5 0z o 11 t 0 0 5 01l 2 H 0 01 (I)) H t m >1 -1N OD 03m ) 00 ci WO 2011/015241 PCT/EP2009/060168 335 4-) 1- H M '0 (N ( toz A0 0 0 o w41) 41) w_ __ 0D 2) -0Q)+ o4 -P o U 4 t(iOtoL 04 p4P 9_ _ 0 .(J L 0 CGD 0 ( M 0 N (N ( H N 0(N G 0 N 0 .00 0- 00N( r. (N 42)(Y (Ul -- z) H4 4) N U)) 0Y WU 4-) TI _ u u u (Uz 0 Q) Xz 0N 0Q0 HZ a 0 =4 z 40 C4 N- 0 (N 0 a) 0 OD0 0 NW z E-1 ( Oc WO 2011/015241 PCT/EP2009/060168 336 M 0 T tt 0 0 0 0 I P .4.) -Ci -C u 41 1 V1 VV1 + co .n 09 co 0 09 09) m (Do0 p1 09)C)c CN(N H o (/ (Do -o090 z 000 0 0 oo L (N (N) () LO Ln 00 0 0 00 T2 12z 22 Ilz 22 P 0 0 0 0 0 00
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WO 2011/015241 PCT/EP2009/060168 337 M 0 0 0 0 0 0 -t - -C) *1-1 +U >1 N 0 N t* Q0 N HN H P4 0 0 z 0 0 Q0 N 0 Nf 00 44 NrN N N (Y)09 =z =z rz rz 00 ( 0 m ZT 0% 0 0 H i Ci ON WO 2011/015241 PCT/EP2009/060168 338 Cv- H 0 I S I I o rd Cd CN x CD -) H I o -) qd 0 H Cd H I O 4O x o C rd (N C, I> I CO - r- I r-I I v-HI r, ,v -0 S CN 4J H4 - H I- - 'rd I rd C r C >i rd Lo | q) | S C> S | C I C v- (N O) Nv cd v- Cd (N Cd -H O> I I rd | Q , , vH CN I r, 61 o> C1 C C rd 1I I v- v- v rd I rd H r ' C - > > > u Cd 0 O v- C I N 0 I C i r, N r -H- r, -H- C> | C C -H- C - v- ' -4 C v- - I 'O I rd a | I (D C 4 - H C- C I N I o I O I C vH Cd 0 I 0 vH Q Cd o> I I -r C-H I I v- C v- v-v- -~ - H Cd > v- Cv Ci Li (N C> I N I o> I v- H I >v 4- C -4 v-- C O C C 0 C C 4 I >1 I - C -r- Cd vH Cd ,C vH I Cd Cd o C Co -- o - , ' H- - -C(N -H- ) v-H I v-H I I 41 I C 4) -P 4 -- , I 0 Cd - v-H > Cd -4 > - G) ) 4- Cv 1> C1 4-) I N I vH I Cd | Cd ( vH vH I vH d g C O o C> o o C -- O o >i (NM .. H I H- 0> H- | - H I H- -H H- ,C -- '- -- , (j C N - I 0 N I - C) C> Q) I -H- I | > vH > v- C C-- d | n > ,- (N | C ( Oq P - v- >v v- v-v I CC LO v- Cv C- > - C -42 - - (N H - Cd v H v H L> C -4-) - O - - - - C | | | vH -H o Cd 0 C C - -H- o> 0 I rd C Cd ]N S (N -H (N I I (N (N Q H u) C o Cd - - - v- - - C I - vH v- Cd a | > v | -H vH vH I H I H I vH O C I (N -H '~0 -H Q) >v >i rd I Cd > rd >i -- ) Cd 'I o ~ ~ u uC)dCC C C 4-) C) _cd - d CC -) C C O0 o -I - v-H D ,Q U -H O C ) C C> I C 0 0 - O 2 v -r- H r- Cd -r- S - C> -H- v- - Cm> I Cd C d r, -- -, I C> v -H I v- I v C> C) I C C v- | C v - - v vH , C> C> vH ' 04 >i(>i CI >i I C I C I C C C> , - C S - - - - - - - -H - 4-) 4 II) co ,C -Q - Or >i rd - Q '-'' - C> C v-H C) - C> -H C C) v-H Cd4 v-C v -1 -d - - - -H C> - > v- H C C v- 'C rn - - rn C rn C rn C v C v C -H v- -H C v- v- C v- C H C> ) m - | M1 C | >i - >i ~- - '--' s -- - Cd - - - C) Cd - C) Cd cn v-H C en C en C en N rn C rn H 4- rm H 4-) I C -H v- H - > v- C Cd w v-H CD C Cd CD C Cd r- - C C - O - C - -H v- ) v- 4 C v- m I o C) '-- v- > -- >i '--' >i '-- '-d - - Cd rd - Cd Cd r-I | >i C) I | I | | Cn C C> N -- Cn N -, S Z c -H Z -H Z -r-H Z C> -H > Cd C> Cd r 4-) 1 1 1 v- 1 -H- > -- a > rd r >1 d > Cd 1> > rd 4 - l- 1 4-) N -r- N N N N N N I - N '-- > ,C '-- ,C' C Cv Cd C Cd C Cd C Cd C d - H - Cd - C S -) - C -H C *H C H I -H I - r I C d -t t 40 v t C o C -Q o> C 0 Z z Iz Iz zz u-o )o )-=o )v-o Ln o o oo 0 Cql r-rLZ aM z= M M z M N M
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0 0 0) C"( N C fl m ')L a) 0 H H HHH z pair~ WO 2011/015241 PCT/EP2009/060168 339 (N (D HD HD ()C D Cd d N4 N4U H I- 0 o o (D 0d 0 009( Hd -H Hn ( 0 0 0d Cd -- I 0 o oN N N H Cd Uw o~- o1 t dCdC C 0 I Cd H (N H 1 (N H ) (N Ho Cd I C 0 N- C) C L LN xi LN CH LN ( 0 H 1 4) a) 4) q) 0d D -0 (D 0 n c) 0 03 o1 . i- (DI I H 1(N Cd H- Cd H N H- In H- (N1 HN 01 4 -,-0 -P -~] > 1 ( i H -0 _0C 4-) 0- Cd 0 ( O 0 I C) 4 4 >1 C > d d Cd H Cd 0>1 ID I C W C) N ) N ( N ( ] N ( i T T 01 I I I I Cd -, ' - ,I H H 10 H 10 10 (N mN zv 0N N I 0 w14 >i A 0 w I1 A' H Cd 0 w 0w QN 0w (N 10 (N NiN ( t 0 -1 - .1- - 1 - 0NH( H 0 Q0C ~ c) - ~ > Cd 0 C 0 -0 o 4 -Q H 4 H C -(N CN - - ID 0N CI) IW C) mN N 0H H:1 H H0 H H5 d ' (N C (N ) I Iw >1 x I I d H NH NA 0w NA 0 >1 d N I 0 U)' 0 cfi 0 U) 0 I (N NP W (N -J U CD C) C) CD -1 C 1) D - H 1 1 1d -C H1 0 (N 4 =1 A I1 A S4 A4 (N - ( I, 4J I , (N Cd>,U 0 Cd __ '0, -- I ', H H >1 H" 0
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0 " H 0 " H1 QQ -1 ,Q ) 0 4 Q 1 >14 1 4 >1 4 L- H ~ H H C ( 40 40 00 ,w m 0 (N S > >1 Cd >1 Nw -,I 4w N d -i (N Cd NI 4 0 4 zT rd H ' C A4 H C) H n N- 4 -I-) I (N S N C ( -0 (N (N C >1 I -- N 0 (N Cd MN I~ I 0 C H 0 0.z -z '- 0 0 -H C -( C (N~ ~~~~~ Cd 0 ( N 0 ( 0 I C w N w O H N H 0 H 0 H 0 N I H I C OD OD- m m1 m >1 - > 0 H m 4 0 N C N C N C N C d H - 4 4 4 (N 1 ( A ( A ( A H 1 ( d ( d C WO 2011/015241 PCT/EP2009/060168 340 t D 6 o do N N 0d 00000 O Ot(0( a) 1 0 ,-T .4-4 o 0 O 0 UO N) -- 1 4- 44 -c- A -C o r H.. 0 0 q O 1 -0 L -J -- I-1 r. t o i -n~ 0 ~ - a o - a) " I o u~ Lo LO .i I OH 4- 01 o1 (D - 0 1 -1 r I a O >1 - S - -M 4 -0 -H . .,.H.H N CH cd 0 010 q1(~ Y) 0 )H d -1-1 rz ON / \ Ld H H 0 04a O LO L NO PU o Q) Cd H - H m0~( vi (0 0909 LC C WO 2011/015241 PCT/EP2009/060168 341 op o6o do ~o oo O 10 0 O 4w .H 0 - -0> (d 0 - )0 -0 (:d 4-) 0- 0-1 0 OH -- - O 4-- -) - - - - 4 4-) -r-| u - -- - (D-1 H H H o 0 -H - U0 0 0 -i O O r-1 4) .110 ~ 0 a) 0 0 0 0 0 0r U p 4 4Jl - -- U 01 01 >1 Z 01 S H P-I V r-i r- N id w - y - H ) - - (Dr- (a4 LO ) ON N 01 (D 4-) 0 0 E 0 -H H 0 (a r.r 0 -0 0P 44 0 Cci) A 01 o n L r [0 [C) * ')*- - H O 01~~~~= v- H N -5 HN 00 0 0 0 0 01 (N 01 l 1 01 z 1 H H-C- WO 2011/015241 PCT/EP2009/060168 342 0 - 4-) co0)L o w 42 v-"I H H *~0 0) :0 00 0 0 0 0 0)0 a H | C CC -|, -|, 4. C) (D (D )) ( D ) 0 ) ~ a) q 0a ) 4 1 75 > H HH 00 - - H - d - U-H 0 ON U N U N OvH UvH 4d O - '-0 2- '-2p '-0P- '-0 - '- 1 - 0 a t a 0 a 0 a r a 0 a 0 - 4 0 0 010 0 0 01 0 1 0 01 0 .- -4 - 4r- . 4-| . (p i D) e r za 2oC v0r 4 0 -'2 '04 H 6 UU I) I) (U( )c) 0 C U U a -4 -- |4 H1 2H Q, H N N N H ~ l tr t > > 4 ) > c) 01 0 0 (d 4-) a C N H ,z= O z o o o m L -1 0 0 O O r-I r-I 0 N H CN N N z > a H a 1 0 ( WO 2011/015241 PCT/EP2009/060168 343 Sop o op O ' 0 -d '0 op OOOHoO H LO O
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3 4> H4 00 4 4-) 04 U 0 rd Va zz w0 a) v-HO WO 2011/015241 PCT/EP2009/060168 344 to 0 z A, 0 0 0 0 0 0 0 0 1 4 4C 4cl 4 4 0 0 0-- o C0 1-- 09 0 14; Qo -P 09 0 (Nj 09( 00 0 0 0 0 0 0 0 0 4) 4z 4z 4z I 4 09 0 o ~ c 719 09 0 0 9 9 4 ~~Q0 09 0. 09 09 I 0 0 0 0 0 0 0 0 a) 0 (N 09N 09 (N 09 UI ( 9 0 9 N ( 9 ( ~~F 0 U 0 0 0 WO 2011/015241 PCT/EP2009/060168 345 0 o 0~ 0 - 0 0 4C41C 41C 41 Nd Cd Cd Cd Cd LO Cdl 0 zn z v z c C :3 - ((N (O (O Q0 (N ( N (N CN ( H 0 (Y) (N N ((N (N ( ( z 0 0N 0 ( 0 0 0 0N 0 (N 0 Q0 o - 10 0 0 3z Q0 3z (N (~ N (DN 4 4(Y (Y ) (O ( N- 7 N - 1( N ( (n m (N (Nl (N (N () ( ( (N 0 z= = ZZr Z 0ZI0 0) 0 0 0l /\ / C Ci x m x m l WO 2011/015241 PCT/EP2009/060168 346 0 90 - I | I - m Cd (N (N) (0( | v- I I U - I I O - C d S ( C C| vH (N Cd N Cd I od I o( - v-H -v-I 0 2 vH -Ia H -I v-H X I > 1 H > C r v-H ( ) (N d ,C C - O I - o I | I O 4 I I I '~ rd I rd >v v- N v- S v- S v- v-1 -v-1 S rd S ,C - 0 v -H - H I Cd N (d 4--H | '0 ')0 > v Q 0 Q a l (N I a vH vH 1H C4 I 1 - v- L L rd N rd -H - | | H - H 01 | I O 0 H 0 C H v-H 0 (N I r-, O li-, 1- U ax a or 0 - 0 I- L N v -| - (N -- r (N v- N v H H N H v-H v- r- N I - H I vH 4 I I ->1 r H (N H Cd I 0 rd 0 rd N I () I v- 4- v- v-v CO ( ( C C C C) I 09 4 I I I I I 0 I vH H 0 *H 0 0 I I oc C C vH SG 0) S H o vH oD vH od 0 *H- > > rd *H- Cd *H- 0 o I -- -- C C C H -- C -r-H -r-I 0 vH N H -r 4 - H vH C( H *H vH - vH4-) u)dCd - >iC v d 4)~ Cl - I - I rd r- S v- -4 4- -) I I -v- 4- 09 (N N ( o -rH (N d o od o" 0D ( | I I vH I H H N0 r- H S D rd - vH |>1 O | vH rd 0 Cd (o v-H 1 > > 1 Cd (N I>1( N I 4- 1 - - C 0 - 1 O 0 vH (N -~ o -~ (N vH 0 I (N -H (N m( | M - - rd - - r -( 4 -| q C-H N LN | -H | LQ Cd LN v- (N I O0 'C - v-H - C vH vH vH vH S H H C H I vH '-' O o O '-' - '0 - -H 4J >1-H-| ( I 0 0 C C 1 00 4-) , O I C S rd v rd 4 H -H r, C v- 4 H d rd 4- rd CC - C C C)o -Ha C od ) S co O d -~ 0 vHO d > Cd I > S > *H 0 co r- - (o _ - o - Ili - O t 5 v- C) v-H C) Q C ) vQ0- Q0 C) 1-H C) 0 C) H -H I -H 14 -H 1 - -H '~0 -H I -H S - C C 0 C - I - H - I - I -) . I 0 ( C d 4- I co 4-) vH CL) ,C ,C -H- ,C (d (N (N rd (N rd ,C HA H 5 - N Cd - N -' N HA rvI d C d '' cd (-NL ~ - rd C d v- J vH C | | -H v-H -H 0 H | vH 0 | 0 0 r-I -P I H ) rI 0 I - r - ) . H C) - o v-H v-LH - r|v-rH - - I - - l m* v-H S n - , - rn r-i o N- rn 'Z rZn Z-in r-i -i r - 0 O 0 (N - C) o co o - D -N N (N v (N > - N v-H N ( -N C '~ = 4 . v- - -' O v- i v- O r v - -H 4J 4J (N -1 (NQ- - - v-H - v-H (N (0N IU >1-v-H I -H I) v- UI C] I v- UI v- v-rn -H 0 2 >10 - 0 -09 Cd -09 -09 --- 0 4 4 ,Q LQ | ,c | Q r ) - H v-rH U)-1 H O r-I N- r- I O U) r I O )l v-Hd >1 H C)N >1 N) >1 Cd Cd 0> Cd 0> Cd d 0 Cd Cd ( N C) C N -r- rd ( N 4-) r- N O -) N 4-) v-H rd v -H | C) | C -- C- C C -0 '- - -| v- C l Cd v-H Cd 0l H] v- v- v- 0l H v- 0l H] I l H x] ,Q S - >1rQ >1, N Cd>1 ,Q o 1,Q >d , >1 C 0> C r-Iz O CY)~ a. ooC N~ -H Cd N C C - 0 C) N 0 C) Cd C d H- d - d - d v- d - d * -l o )=o )o 0 '0N 0 N 2
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N N -r- 42 -- , - Nd -H 42 - N 0 C)-- Nd 5 - rN N -- Nd C '- NH '-' N , .0 NHa C -5i , '-' -5 -5i '-' -5i -- s '-' -5i -H -- E c - 0 0 5- E N V C) m- C)L t~ I L) H- I C) 'O I -rIH - I I N I -rIH I2 'zz z )-ojT o 0 -Z -Z -Z o zz Hz zz zm zzz zzz O N N N WO 2011/015241 PCT/EP2009/060168 356 | C o i I - Cd 0 - (N0 v 0O -H o O I C" l -r. 1i 1-1 0 O - V 0 ~ Q) I 0r- d G I | rd Lf -H -- H LU | D r, -H | Ul | v r- Cd r-1 v- - rd V (N >N [ - C 1 >1 -H | | V H H (N I v-H 0 QD ,0 vH U vH M' I U vH v- U I -r- - v- - r- >v Cd v DC 0 C N I - (N o o C C vH vH- C ,C r-I -r- ,C | > r -r- V, v -H C V, I ,vv-| S l r G I Cd V c d V,1 V r1 -l -H ,V 10 , E o i4 -- 1 O O 'l v- - mD > - C V Cd U >1 v- -H v- V v- -H | C -vH V - 'Od - GD | C d C' | [ Oi C' rd v- (N (1 0 - L H rd - r - ,V Cd LO v- -0 L H U r r-I - i - r- >1 r >1 0 v- N I 0 ( - q I H I -- v-H - v- I ' U - v- | U Cd (N v I >1 0 I v- >1 -u A- O C rd 0 U AI A | o -H H Ci 'O - -H -0 -1 Ec C a > o S U ( 0 -- U V Cd ,C r (C >1 l v- rd rd - 0 v - r- | V ,V --- -- C C -r- U - lr I Ul I '~ 0>1 I m (N V (N VC I U (N I (d ' I - rL -r - - LO) -- O - Li | v- U r-I v- I r-I (N V I 0 >1 H 1 '- 4 v- Cd S -lI |Y - r- I r- H - r-I 1Dv- v -H v- ro v- N I v- C C C I - | r - | Cd J- -, 11 -, I d- - - H I 1 0 v- C I -r- I -) V v-H Cd Cld M - Cd 4- v -H u v- x - V d' 0 -1 r Cd i- LC - P | O 0 -H vH U 0 V VP ' H GD I C U GD | C V 0 GD - ( rd Z >1 - (N 0 o v- v rn) I v, - U rn I Cd 5 U rn) v S 0 - 0 -- 1 H- >1 | U6 H- v - '- U - Go o I (N V -- 0 >1 1 -- - I I -H CM '--' rd 1 -H I LO l Cd | Cd Z Ul v-I -~ N Z l GD v- V '~ Z H I V I C d I V I Cd -- I 0 I C GD -r - | C v- N S - 1 o G C U- -H G o v- Cd Cd 0 ( C r-v-H - -, V -H >1 v- -H I -H V C I - - : rD I U I - 1 -- U C -r- 0 C Cd v- I v- vH I v- I C' I Cd Cd 0 -vH v-I GD U v - GD 0 v- GD -- r-|-H S l>1 GD v- Z v- -r- 0 GD v- v- v- >1 LU Cd VC I - G v- 0 ' I >1 V V V V v- U- C C v- G v- I V | Cd Cd >1 v- GD GD Cd -r- >1 v- v- Cm Cd GD U S VC G I V I ,V GDr I | v- Cd -H V - - Cd 0 % V - D GD A- -H- - c S HN '--' 0 0Q - r-N --- CdO v-Hc r -- EI - O O --- E c -' - - I H1C>1 (N -r- '-' | |( N 0 (N - '- A 0 (N GD GD 0 a c N O e0! 2 O--1e o IZ 0o o -z e 0 \ /\ z O C~ N N' ' N M N r~LO WO 2011/015241 PCT/EP2009/060168 357 r-4 0 .U) > 0 >c 60 60 >0 030) 09 09 0 (D 0 0 09 (2L (2 9 o 0 -0 -0 c 0 A 4-) q) 0 0 0 rlu 0 ) (D) (D C)) p4 U .H H Cd m 4- W 4J H .H 0 CA 0) 4 -C (Du ) -1 4- i-4 >1 T Ln N N 04 4$a 0 1~ (Y) wa c.'n a)) 4 r. 'T -1 *'-1 r)C Y rd 4-) X X 0 Q) x oo (4 00 0 m1 fi ZrI N0 z 1 WO 2011/015241 PCT/EP2009/060168 358 0A 0 0 0 09 I- oO oo o) 0 00- 09 I--0 , tw Q0 4L) I-- Q0 -P 09 -o090 H QQ L I 00 0 0 00 GDD 00 Q o -4 , za 0 0O Q4 o90 (t)) I CA v-] (t)( -12 M90 90 a) 00 09 0 z Cz Cz z WO 2011/015241 PCT/EP2009/060168 359 I I ( N I o G]( I H I (O I -, 0 N o rd I I 1 O ' 1 -H S N (N I C C 0 3-] (U H- I H -H -H 4 D - I 0 0 S I 0 I I N .N ( Ut rd ) - (N rd H- H 0 C r, H 3-1 H C) I - 1 -H -H H -' 4 I - r LO C4 |1 | n N -I H I D 4 U 4 N -P I H >1 - H H I I H I H - I H >1 3l H (~ - O , H 0m oN H- O-) 0 H I H cN > I H- - (U 4 I | t - (N --- >i r I| H- I | 00 ) (U ( L C (N | H | - O >1 C I - H -H H -- >1 I (NH .. U rd S -- - I - H C | | | S -r-| (U ( rd ' > H- U) GN -r-| C H- C 0 I O 4 Ln .I r-1- - 1|'0 0 > NU 3 d 0D 0 H4 H I t (U > S 4O I 34 LN - - -, ( -H H -H -r- I (N rd -- , o I 0 I Hr - ] 1 4 1 t mN I C - H-1 N C C 0 4 ( I H 0 - (N d I -H (U 4 I S i L r-|U H v - ' - ( r, S Hr 34 m Hr (N I H OH ( 3 > H t H 4 -r- I - | | >1 . - - I r1 - 3-1 (N 0 (U ( I H- I I L N > HH C ( I 0 N H H H H S I H I - 0 0 I 4 -) H-- -, N (N C C C) N C U - I -- , H- 0 O - H ( d H 0 o O > N H H- H -r- I (N LI H 0 3-1 L3 -- - - - , , H U H I )OH - I H 0 S ( D - 5 I | H M | C | -- 0 O n N ( 0 (N CD 4 eN H (U H CD C-I C) I H C - H H ) - I S w 1 -H H- 0 r C - - 4 H 0 O rd O IC C - - (N> u I CD ) , ) 4 O ) - 1 -1 - H C I |4 I ( - I 0 (U 0 ( (U ~ S - I H (N C) 44 (U 4 4j Hl c] | L -\) -'-r-|0| rr >1 t' -- m- H > - | C (~) or n - I -I 0 ) H (N U -J o O H (N i r 0 4 i - 4 - o H O C) ( - r-C S r r Nn I I H I I i -5 0 I - r- - | A 4 - 1 O 1 4- -H O0 - - T I - H ) U C t C H C I ( I ( S 4 H-I H- r-I H I -- | - H S LI 0O C --- L Ln C H H H LN 0 LN (UQ0 C ( I 4 (- ( >1 - > 1 t' ( 'R 4d H H 44 (N ( - ( -- C m - ) N Y H 4 4" m H 0 4 0r -H 1 ( H r '--' N (' -- ' - I r! U- ' H rI S -J S Y ) U) C O N -H (N M (N 34 O 0 H - -H > 0 H- >1 I 34 I - I C 00 U) ' ) - C - -, - -- , Hr- H- | H- | -H- | -H m 1 NU 1 x (N S3 N C) (N 34 tN 34 N (N (0 N H (U ( H >1 H- 4 '- 4 - 0Jd r-I -i - I - - z - (d - md r- | H L- -|H (N L H- -r- H- N I N (U ) 34 U) H4 a) H4 H 4 H H 34 H U (N ( [±1 -- '( - I I 4I -H I -H -H -QI - 0 oQ - O - (U - 34 0 -( 3 S L) r-|) U) r- Hrd t ~ 4 ( 1 0 H 0 C0 ( C ( rd ( 0 ( -H ( | C - - ' - >1--' (U 4 H- >1t H- - -H t- H- LN 5 H- LN (U -' H- | -r- | 0 (U -r- C) H - 3 H - H (U - HO0 rI H I rdH O 1 ) rd 5 U) 4- 5 U - 4 rd ) - o >1d( >1 N >1 (U (U 0 N C) 0 - C) 009 -009o > 0 N (U N (U N 0 C) - (U (U - H (U - I H - | C C 0 C -H C -H r '--' -H - '--' r-H -- '-- (U >1 '-- rU (U (U I (U 31 (U 1 H- I 31 H- I - H- I (U I I (U 4 F, To 0- o o, o O / . o=r )o oK /\ /\ / / \/\ (N 01 N 0N 0 m ~ C fl m U)c) tO N a)i o ea c q Nc c cqj d N x M N N M WO 2011/015241 PCT/EP2009/060168 360 H oo oHH WLC) .V Od k (d Co 0 -1-r 0 0 00 ,25 42 o 0 0 O d - V r - 0d 0 t4 4- - 0 -0 0 r -r-I '~ ') ~q ,WC oZ a) o ) -1 u J .Hi I N 0 0 0] 0 T H I 1 H tH t 0- .I H 0 -0 rI .1 0 .)Cd0 4-) Cd0 4-) 0 0 s H s od Ia-1C -C H-elC - -ri C Nq (D >1 (D H4 Hd). N diC] HN C]N x 0. >i1 .0 >1 co I1 04 04 00 cc) a)z z 4 / q 04 0 W rq H NY cr p CN COiC4 * CO4 Coo 0 4jw Q) 4- di NN 4. N N M M M M E ) a)4 o 0j aY) Or cii '1- 0 OD -. 0 0.0 z N (t) IH N W E-1 W WO 2011/015241 PCT/EP2009/060168 361 43 LO> LI> LI 0 to 0 .H . d 0 ~ 0i 01 -d- q - )- q) N 0 0 F- 4 F- 4 u a L 4-) N 4-) C a) a) 0 ) rd 5 >1C (1) o (d 4-J (d 0 (d (N a4 04 w 01 H) 0 bU ) v-I v-H 4--I H z C~Cd P442 LOA 0 NA zrz 104 C)c WO 2011/015241 PCT/EP2009/060168 362 I P 0 0 0 0 0 V W-Ci 42i 42i 42i 42i 4 q ) (D (D q)(D( S0 009r- 09 -P o -o 0 09 09) 0 o 0 *- ) )cno ri E-1 cn M 0 CfO -409090 09q 0900 * z w 0 Q0- 10 0 0 0O 42 0 0 0 0 0 0 0 90 90 Q) () o) N) N) ) m) o ~ 0 0 0 LO) QQ ai4 0 0 z 8,/ 1I 0 H- (\J (n - LO) a) 0 C'J C'J C'J C'JN(NC z C'J WO 2011/015241 PCT/EP2009/060168 363 0 x m 0 z' A' -0 b0 L I , -P v- 0) 1)(p 3 N -4 N N >14N 4 4k2 4-) 0 Nd _ _ _ _ _ 4 II (9 v-- ~0 >1 0 0 0 4-3 c3 I00 >1 - ul- H -1 r0 d ON0 0 0: NU 00 Cv--~ ~ I v-A 4- C) ~ 0 (1 -I 0) r o u N) -A H U) I 0 o 03 I 0 m 030 1(H ca HO -03C (Y) (N 00 4 H z~ N) m/ N 1 0 N' (D z v-A -,-13 42) 0 0n -'4 N >1 00 0 I I S>10u N' Q0 0 4- N -- N 44 42 >10 N (o N0 0 ~N I 0 42) N rx4 03 qd) N N-v 4 0 Q >1 424 444 z z 0 rz =r z-z N "Z P1iZZ ONj t=o N0 01t 0 ci, Hq0C C z HZ 4 x4 08 ___pa U__ _ _ __ _ _ _ _H_ __ _ _ _ _ _ WO 2011/015241 PCT/EP2009/060168 364 Cd~~ 4 xI0( 4 1)0 0 0 H N C >(d C)0 0C Cd4 Id q) ud I 0. >1 4Cd I ( >1 od i) C) 1 I N - 4)O . -a-a H Cd0 ( (N( D I1 a) C >4- CdI Cd 0H 0 4 4 4 H (N > 1 1 01 C C d I (N I (N (N0 0N 0 -5 HC Ht - I H 4 (N 4 HQ4 C- 0 0 Cd m Cd H IH0 I0 N X- I d I a ( NN ( I I Co 0C 0 4 > >C r . O (N -H H I . 11 -) 1 N -C N0 N q( N (N I -C) .4 *-H I T ;- T (N~ 0 (N H c Uo H3 C H) I r -, IH Cd I I o 0 H I Cd C 0 m I) u) H - 0 m- 0) H H D H ) ( H -P o H 1 H C H C 0 o1 m10 uN uNN H H N * 4 4 4-) -,1 -P H 0 d( )H C I ~ ~~ I -) H( (N 0) .- I (N ( u H 0 H1 CH 0 00 C 4 4 - d >1 C d t 4 (N) I (O 4 (N co C U I *v H H1 H0 d H N H (N >1 (N H(rlC C dC - u 1 I m ( d ( d I 0- 0I 0 C (N n mN 4 Ld nI I 4 (N H Ld Il Ho Cd 0 N 0 a) wd (N (N N ( D d H U- or 1, C 0 H H.
4 - C S I H I H I >1 n I >1-H I >1 Ir m '' d N '- -. '' C C Cd ~ r C -~ C Cd I) N Ic - 4 'o 0 ) C - ( H U d u) *H 4 -P U) oN H) Il 0) HH 0- H) H) 0 D - 1) (N u- C HP C m1 HW 4 uH4 C H ~ H H - >1 - >i (d - d 0.4 - d 04 - O ( d >1 I >i H - (N C (N OH (N N C (N N 0 (N N n ~ (N 75 C- (N H (N H1 t - (N d -o rN d N4 (N m H 4 4 H - (N 4 (N 4 H (Nt ma (NtH $a r I S I 0 - C C 0 1 >1 0 I >1 0 1 4 L- I 4) N H - N - N N4 - (N - ) Fi L(_)0 N- m) N -N N '- d '- o Cd N -4 HI 0D $a4 C -~ (D X (1) > 1- IH I H >1 I - (N I -4 I d 4 0 4 0H 0 Z (Nt 0.4 ( OD Q4 ( OC 04 (N 03 Cd 'Z Z7 ,z ,Z 0O 0 01 0 o 0 Q Iz N Z IZ =(\ Z 0 0 (N N 0 H N CU) v O z WO 2011/015241 PCT/EP2009/060168 365 I ' O N ~0 00 00 | o rw 0O 9 ,03 0. O5 H 00 G)o 0 o H aH 0 o0 0 1 0I o 0 o .
o vS GD U u T I o o p H rn C N .I5-I - I x O | H I 1 N S o v--I o) 0 5 I >1 C) vS I S 03 (z -0 (9 0 O (0>1 0) 0 0H 4J H 1 1 ,-- I - 4 H g 9H M M 4 ca. (i H- I W 0~~~ tq ~ .~~~P .~v U 4 14 v4 1403 NW 0 (N 04 0H( 0C a) OD Z-T / LCO WO 2011/015241 PCT/EP2009/060168 366 oP oP o ( o r oP do ( H Q0 H) H) U m w V 0O OOO C O C O O -1 .Ci., rio 0) 0 z z z .r 0 ) 0 co 0 z C 0 0 0 0 0 U u 04 4 H (N Ha0) C ( 40 0 0 0 LO H EC H H) C o 0 o o r o - -,j d -. LC 0 L0 L0 L0 X,~ C C C C 4N N b-z -z 9i (d H n CN 0nC C C- O LO O L 0) H H H N C Z n H 4 I I I 0 0 C l M 0 LO w0 I Nq '0 (Nl (N WO 2011/015241 PCT/EP2009/060168 367 odo oPo op oo o6o oo oo LO) LO) a) Q 3l1 L00 0 - U r- 0 .C H. - -H _,_ .- _D - - 0 - '-0 0 Cr -r-1 -C .C rd di 44 H -H 'O 64 - 4 4 -H H4 -P 64 - 64 - H -0 ~ ~ ( -H D) - -(>DHD' '0 C 1 - H o- H Q -H I U U I H N C 0 - -C - 4 -) t H HHc - n n in 4n (n 42 e4 2 LO Q 0 4- t ) ) > U ) H N N N Cd M N N N un4li -AI-> ZI m 4 o ) 0 o O OO N H HLO LO LO LO LO LO LO 4-N .l q N c 4c -Is NM' N M' N M' M M 4-) xx -TZ-T: 2-I Z-T: Z-= LO Z_ /\: zzK C> 0 oO C'J Clj %D C'J N~ X ~ nil X Xrz WO 2011/015241 PCT/EP2009/060168 368 - oo o6o o6o o6o o6o oo oo HL 4 LO C 00 1- Ln 0 to co 0 (:4 7 :4D a 4 -0 -4 V0 . O\ OOO O O -0 . .. 0 .c1 0 1 .r - cl ocl -C -C H ( 0T LOi( 0 -- - -H H D u 0 'J 0 r- 0 r OP > m > a) O > -H H~~ (D 3 t U l -H > 1 -d - > 1 U 0 , )u4)-i F 0 LO V a - 2 0 N 0 N _T 04 rd H H4rd4 4 u >1 O C) LL CdM 5 M M M5N M - r z- z- z-r z-t z-Hr 0 0 04 H/\ C)Cd Prd H. -1 L CnL O LO O l 04 Cu >l 0 Q= - LC\ Lfl LA LALA LA 0 N N N N C"I N 0 WO 2011/015241 PCT/EP2009/060168 369 0 0I 0 0 0 03 4-) 4) 4-) 42 4-) 4 4-) 4-) 4-) Q0 m oo Q G' (3) CC)( (N) 0) () 03) ( C)m - ~- - ~- ~ GDO CC) 0 N 3 03 03 4 4-) 0 (DO N 1-- 03 ( 0 0 0 0 0 0 0 0 0 0 440 (n (n (n ( (n N3 ( (N Q ) Z-= C)m (9 C) C) C 4-442 0 K Q) z In Q) b/\ \z M = Z aIZ TZ TZ x C14>o - >=o 02 0 0 0 z z z 0 N - c' ( Cl N l WO 2011/015241 PCT/EP2009/060168 370 0 A N (N (N N (N N (N WA 4- 4-) 42 42 4J 42P4 + n(Y 0 D C(N (N -H -H m> Ln H P4 0 H CA C)C> c 0 0> z 0 0 0 0 0O 0 0 10 -- l A La (N o co QC C 0 0 r4 co 0> 0> (n Z-a T ZTZ-T Z-T LO 'zJ ZT Zf 0 \ - Z \Z 00) 0 1 C Y-\ OD LA0 w (N w 0 O NL% N %D N N N N N WO 2011/015241 PCT/EP2009/060168 371 0 OH~~~C 7HO ' O HO 0 0 0 0 0 0 4-) G9 C') 09 +H C5 C5H 0-9 C'D C- 0 0 0 C' LO CIO 09 4-04- 00 0 09 (Y" 09 ) 09mm Y ca (Y) N9 G) I-- 0 0 -H 0 H oQ 0 _ 1- - CI 091 -0 09) v-o 0 0000 0 0 0 QQQ Q 0p v-H 091 v-H v-H 097-v N Y)CI-\ N) 0HY)G 0 09 09 09 09 z N0 0 8
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lo 0 0O OD0 0 9 90 0D 0D 0D 0 09l %D 09l 09 ClC~ z z WO 2011/015241 PCT/EP2009/060168 372 0 ) 0 | ( I U H N 0 D (D 0 >i c H -rI - I O C I N CD 0r - C Ln S ) 0 --- r ( N N O - 0 I ( C r I -H C D LO - LO ( LO | Hi Q0 H H Ho N H C C H C-H C I - - rI 4 - - ' rI 4 1 0 -- N 1 S0 C I 0 0 1 1C 0 C OH 0 I C O N) O C H - (N -H I H t m H CD N H H rI > 1 -- I -rI HD D -I rd I di H O -H) 4~ N N > - > N Cd | (N H I C '-0 0 ) xC 0 4-) | N - C I c I -- I I ) I C (D I - C C 0 C> C -H (N I - I C N o C H H >1 H H C -(N C H 4& C I Hr- -|_) C- 4 '-- | -|_ - | -r- rd 2-H 0 N H- - ( 1 - C I (N 'C C N ~ C H N H H H | N H H H -I- C - -I - -C - (N ( C \N - I 1 d H cN m, o C o o 7 - 1 -H .. 0> H ( C -1 C I | N o | o I C o I H H ' 11 u0 C mN C m4 C H H -) H H Q | C - H N > -H >1 N - >,i - o c, c 4J - ' C 4C C 4 C - -C, - -C4 I C - (H C C 2 4 4-) I 0 4- H- O 4) rd 0 H C C C I D N N o - (N N m> C o 0 Hr 1 o C I N >1 - >1 H H H -- H H H H I C0 I ' ' I -I C I ' I C 4 OC 0 >1 o I - 0 d d 1 -C 4 0 ' H -i-P 'C C Q Q0 I N DQ -4-) -) 'C S C -H Cl H r - - H C 0 0H -Q 4 ki d crl - -Q u u - 2 4 C C - - rd S - o o - H - H r0 - o 4 J - >i N r-1 r C -1 r '-0 Ci C -1 C Q 'H C N N I N C I U C 1 0 I 4 C I U C a r C 'C - O rd - ~, o - 4 O - Cl M 'C >, - H c H I C m C 2 4 U) $ U) C C -1 U CLO C]N r, LO C 0 L r 0 (N C r - -H -- 4 C H- | -I H -r- H H- C H m- - H- r- C -I I I m - - - S cN - ' N - C - 1 4 D- ' 'C 4# C % H- I N rd - C - C I I rd I H C >1 C >- C 'C r N 'C C (N C -H 'C C N ) CC I - H - H - S I C C - ) H-1 - Q 0) C C o > o C-sr' U) o ) r C - H (H - 4 H O C H 0 C - ' I (d - 4 CD C 1~C0 ~ H 0 I C N I -- I H I > H I 4 - 'C 'D CI m C H I C H C 2 4 C C 4 I I H - N -- -n > -I >1 >1 4-) >1 C m - OU)C 4 H C N H C C H C C H S N 0 H C - 0 I rd L-r 4 1-r-| r-| H H C r H 1C - | H L rN H r N H H I -P o 4C C -P H C4 4J o H - 5 I >i -' C H H- C -H 4) C >1 4) C mH 'C o 0 H O N I m 4 H m H 4 H I - I N O CD - I C - I C N I 4 N I '- -, 'C d N C 4 - m 4-) CO D CP -d 4 4 r 4- -H O - N C H C- U) m l C l N C4 Cl -H Cl D -H l Cl (N U) C C C l rd 1 0 - C - - (D C- C ( d 1 C C - - I d U 4- C 4-) $a H 4-) 0, 4-) 4-) 4-) 4--' 1 md (N o Z-T z o zz -4 0 'C I LO P u z N >o >o >o >o >o >o -1 0 0 C 0 0 . u OD 0) Hq N a) v) LO LO LOLOL 0 N N NN N~ N WO 2011/015241 PCT/EP2009/060168 373 I I rd (d N a9 O O O - 0 0 o q) - I q) I (N I I u I ' H Nt' r H o r 0 (N - H I - I I I I U t I -1 0 Go C 0 0 o N o H OD u I(io - 0 O O I >1 O T 0 - T o o 0 N V 0 (t H 4 N - C)t *H V N Q '-' - > - '--' Nl N 0 (9 (I) N C I -( d N | C S Nd I OH I I u N 0 H O 0 O V N 0 I N I I >1 I| I - NlI - N L N C L 0 (N ( 0 0 N - N - H - V - H N U H N I H (N 1 1 I t I 0 N ' 0 N H C> -H N -H 0 H - I 0 - C 0 H N C Nl 09 C 0 N 0 -, H 0> N Q - >1 N 0 H H N H 0 U I -r-5 k N (N 0 -r- I '-' S - I '- C >1 N) Nd H I N ( 0 N H ( 0 H U H V U 0 V H H | H H -H >1 HO>- e - I - U H- rd - U Nd 1 V H > I I H N N (N 1 '-, V N C N 2 (N H U VC 0 H U H (N S- -H C | - - -H V U I H > N Coo t o 00o 09 N1 0 9 N 4 (V - -r N H I V St I V -r-H >1 -I 0 - N H - - d U V 0 V- H H1 N >10 H - N N0 V V 0 N r1 - - N 1 4 -- N I SQ -- V V -5 1 1 Co -A 1 H g| NeH . - (NH N V . (N (1 V ,V O I 09 H, I I NA SD F! V HA o I Nd H H - N H- 09 C (N H- 09 V H (N N - N N >1 H I >1 H 0.1 4 0 I H 0 V - '-' V-- NO | I 0 0 0 U V H -' C I i d | -t - | '-0 - - 0 0-| N H H- H H Ndo H rdo 0 >100 >1 1 >100 C I 9 L0 U C | N | | (I V4 V N V4 I rN '- >1 I r- (N (Nt V 0 V N V 0 N N H I N N H -- ' I -H qI) N 0 o - 0 E H H - 0 S - 0 S C N S u S N I I N >1 N I I N I N N H O H - N C Vt'0. N N 0 0 N ~0 N ' 0 '~0 N I I 0 V r -N H I I 0 I -H 0 - I - H -| ~ N UH -, V H N HH -4 A H ,V C N H -H C , I d ' 0 - -H U '0 1 U - -NH U V (N U S H H 0 N S I I V 4-r - 1) I q) H I H -- - (N - H LN 0 0 o rd N 0 I | - U H r-, H 0 C -H H H N -I 0 >1 0 (N 0 >1 ' H I - H Nt H I t H I r U C C U I a4 N r - ) V >10 I N -- o 5 9 r - 5-5 0 0 o 9 C 9 i C C N S H S N H N ) | H V H C I | r N V N N V - U-(0 -- U 0 - N - - -H I N I 0 I N H N N rn0o N H a 1 - H1 0 N . H 0 N - V 0 I 0 H 0 V H >1 V I N I U I N I H- I H N I | | I I | H >1 . H - >1 H N4 0. r- V En 1 9 U rn (1 0n C m N Z 0 I n -M N r 0 N L0 LV -5-| L V LO - 0 I -, Lo - 0 L H-N H - H '0 - N 0 H >1 o -1 H m -0 -a V 0 - -H r-I rn | C - C H - >1 -I r H ( N r-H Z H -I 0 0 5r-H 5 - e V 0 - 0 N 0 - 0 0 - - N 0 tO - 0 V r- H ( -H - N 0 '-' 0 d -H 0 - , ( U9 H n -09H rn - 0n Ni - H -,r N (N Cr 0. N --- | I N -I >1 -- ( -0o - V~- o - - - 0 H - C -1 'Z-T 'Z-T: Z- Z-M , Z-T LOC) :z-I Zr z . 0 LO %D r- 0) LO LO LOD LO o (N N N NO NDc z N N M N WO 2011/015241 PCT/EP2009/060168 374 I I I I I o I I O I I Lu v-H (N(NI (N I 0 I (N I I| 0 I I (90 O [- ( - N o v (, N o0 a 9 vH -H 0 v-v-- 0 0 1 N ( i .1-H I u -Hi H (N -H- (9 (d C (N ( -- , N 0 O) M - (1 O V 0 -- ' 0 -C) C - VQ I V | | (N ~ - (N I (N I -H (d (d rd v-H v-- G (N vH v-H -- (N - C -, | | O - I H vH v-H H H (N ud - - (N ud o >1 > N N H H N H v-H mw .-C H r I C 0 i 0 V -r*H GD -H GD G C ,C (N O G C U -- '~0 'O I O V -- H I 0 S C) *H ( -H ( -- '-0 Q) D - H N -- H oU H 9 0 (, vH O 0 Ni ~ ~ ~ ( 00H0H ( O 9 ( -- O -)- O -W- C -) H - O4 C -) 0 H 9 9 ( 9 -H N 0 -H -H V 9 V ( V ) v-H I Tl c Q ,. (d Nv I lI (9 -r C V ( 0 Os 9 0a v- Os v- (-, N 0 rd -, (N r 0 I (N I (N r-v -- H O '-- N v (9 C v-H - >1 N ( *H ( 0 u >1 N I 0- oC GD o1 1 ( I1 -r- C (Nt I v- I - 0 GV) U - - - L- - C - | ( v- V -H CO I v v- - ~ r- -- , (9 '-- C N (0 - H - | C I C -- (0 O GD r 0- - O Io N O N v-H I -- N v- v-H Hi - N - N - i C 2 ( 0 C O >1 C g| ~ ~ ~ ~ 1 4>1 C O r- O r- C >1 I -l 1 -10 C > u -l C1 (9 C) ( 0 -H I G- O ( ( -1 Q 9 M rd W ( C - C | 1 - T r1 I o r . G I 0 I 0 (9 V -H - [~ I V (9 V v-H [ C N -[ ( rd W v- v-H (9 ( ( rd H O' -' v- 0 v-- 0 I N V v- - N VQ I N I 0 t '- (N I (N 0 0 v-1 (9 o~c M- Ca r, 0 - - H [ -I M o s--l -H GD vHHN ( - (NJ GD v- U -P I -I O v- c" v-c i (9 v- (1 (N 09 I (9 - N ( -N V - (9 '0 GD I I (N V rI O GD C) GD C) '- (N N -H | -- ' C) '- I H *Hl I - I - GD H 0 E v- v- I - GD I 4 v- N - I -vrd >1 N --' I -- N - > GD G (N N VC 9 0 G D 0 (9 V (N , (N I H- I 0 V 0 ( I H T N, M -d M - - >- -, .Q 0 . -r- r-1 r -I -H N V V-) v-H v- - V- (9 L * v-H 1 *H LO v-A ( d H- V 4- ( 9 rd *H (9 (9 - o d rd (I H H -' O *H C '0 I r O O V '0 0 '0 0 ( r9 o E I I , -- (9 r9 >i Q I - I v- S N ( ( (9 L) D 0 >1 S N ( V r- N> H N> ' 1 *H '0 v-H I *-H G '0 1 -H X - - C C (U I N S I al ( v- S I I (N Q v- v- -H- r- *H ' GD I (D G V C v- (9 ( G I (9 0 v- v- (9 r- (9 -H v- -- N r-I ( (U | -- (9 v- -- , N -' - I I V H O - 0 - H - - I -H *H H 0 I GD --- (9 - (d (9 v- i V. r-- (d (9 r2 al (I v- i V. GD | f N rG] N V v- ,C (9 r- -- V CL ,V V v- ,0 (9 | (9 C) (9 L) (9 (U | (9 | v- | v- V | (9 -N ( v- -H H *H C --- (U - N> Ha Wv- -- (U C GD] 0 '0 - (1 (9 (9 GDrJ F I D (9 (N N 5 (N rGD E L) -H|V -r|L H C) L) -rH GD v- . L) H CL (N0 5 GD I GD v- v- Ni v- H-- '~0 GD Ni GD v- Ni v - (9r - GD GD Ni> - ( | -H v-- rD (9 v- (9C O N rG> v- rD v- V. Z -ra ( % v- C) *Hri -ra ( GD N 0 C) - C) - V GD ' (9 GD 0 - - ' -- , GD (9 - 0 VQ --- r- - H VC - -H (9 - (I C) - *H C) * -H 9 GD] *H (9 '- v- '-' v- (., GD (9 *H D] (9 (N - (9 (N GD (9 *H C)- (9 (9 I - I - (9d C |>i (9 C1- |> --- | |>i -- |>i (9 Z-= Z-= Z-I Z-I: V C--ZD -- Z9 9~ -9v- ) (~-Z -- ZV Zz rz ZT ZI 0 0 1) o N0 NO NO 0 N% N N ~ %D N ~ N~ N Nzl r n WO 2011/015241 PCT/EP2009/060168 375 HD H m \ - - - 0i 44 -) - -0 N'~~ N I 0 >1 0 I c u 01 0 - 0 0 Q - C ' Ic 0 u 0 0 u 4-)d 0 4-) -H ) - () (D ~ 4- 4 -) GD,- 4-P 4 n (d 4-) M (C M N (NI (N 0- (N (d * a H 0 1 mC) Q0 -1 (0 . (N 1 -N =d GD I 4 G C) GD) GD) 0- NrC C g) 02 1D -H ~~ C11 w Ni I N ) ) 0 0 4-C) S ) 0 4- H > ' ' U ~ q (o (D H(o--,G H G >1 GD D i N 0 N x1 0D( 4- ) V , 1 - H 4I -, ) a 0G N V~ N mN 4 N m N Q0 N z Q0 I 0 d 014 01 01 V 0 Vc, -I VH -- V DH (N) I r, Z I 4I I ( , 0 v -n C' LoGDn L .r l - ( C~~- Hu) m C ' H H H H 03 $a V I 0 V $a -P Ni = N-M GD S D S N D-i H== (N~~~~L 001H 0 0 10 C VO Q)1I H 0 I H0 GD~~~~~~ C' C] S I N4N ! I V N I S I V ' GD~~cy C) - N o DONb~H 4 D 5. a)DH I D C 0 4 cq 0 - ~ IN - .) N z 1 ' D 0 D 0 DM G WO 2011/015241 PCT/EP2009/060168 376 -- -i 6o odo do o N OO 'Q0 0 4-) H00 0 0 SA0 . - U -- U- H - a .l . > . 0< El (9 (i 'H 4-) F H H T u 4 o-> >) .r - r> - 0< 0 0 0 S Oo o ) o' ' (9da) . - -5rHH- iu -- - r-i >.1 u 1P H0 HH 'U 21 H Uj Uj 0HU 4-04<1 0 4 01 <( H ) N U) H HH P4 -o o 0 0 N 4 4 Qfl N 4E 9 p44 4) 0 r. (d -0o -A Cfl H-A H H - N, N N (0 N- '2 -)- Nq NNN N U0 ( 4) 4-)xl[x [Al [zI [z 0 0 0 t=oC to= LO 00 to0<zr = 0 co N n 0 0 Nl (N q (NN
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WO 2011/015241 PCT/EP2009/060168 377 V - 6o 6o 6o do o 0Q -d Cd m A -T -H -H H -H dC 44 0 tu u HH 4~) 4 C H~. C) U0 -d -d t o o o o o t 4- N N~~~Z u ,uz 0 0 - l 0 0 I0 a) 014 01 4-) (d 4 u P4( 014 i 014~ 0- 01 )) C) .. 5M (Y) (Y) - C ZN NI ZI Z Z) I 4I Z OHr OD O o OD O cO Z ZZ 4- tC N L) N i C ) ON N AA a4 08 (UT (U ) 11 0 0 A A -fl N~ y 0 OW 0 OD OD HD OD HD HD OD H *H N W CD CD CD CD CD 4.z WO 2011/015241 PCT/EP2009/060168 378 6o do o\ do op O\O LO 0 0> 0 L 0 0 -0 - -0 0\ u) m u c 40 ,) Zo d || P4 o To( ) -HU - = 0 -H 4 H L 0 F0 U -C, -o 04 ok - ('2 q) 0 M u H H - D uu) N I t.05 0) H t1 7) H 1 t a u 5 (* O0 4 0 0 014. u T 1 0Q4 0 0 C 5 (NN I 0- O )- N (N 0 U) >1 >1 >1 >1 H N o U oH - DC o o00)0 4 H *H /3\03 /3\N 0/0\ O 00 1o r-0 >o0 O N C,,oz 0~ 0 0 0lo o 0 03 Ct 0 CH N Cf 030 zC tC WO 2011/015241 PCT/EP2009/060168 379 0 op o o H o oo 0.C 0 A 0 -a ~~ ~ p - . - C) a O o I -H O( 0 - '~ 0 >1 T > P 0 0 0 N H- -C O + H C CL, - - e e- -P u - 0O L -a -s o0 o ta N i f) Q l /\ O >1 t . 1 -0 H > z 1 r az aw E-1 Mf tl)0 (N H N GD Oa 0 00L U) 00 Q4 0 0 Nd N1 ~ N .- 0 0, 0 .H -H 0)0 0 > 4- P .~ c N P4 CO4-) N u.C 4-) [A 4-)1 XCl U ) 0d z H 04i 04 if 0 0 d > N m5 0 (d C) N m- z AI Cd E-N 0 N NN II) 0 NO WO 2011/015241 PCT/EP2009/060168 380 m 0 t tt Z xi: o 0 0 0 0 0 0 0 I -P- -C c,-C C C u 4j -0 _0 _0 V0-X (D- 1) (D (D'D) + 0 (N (N co 01 0C Q0~ LO D L >1 Lo) 0o 0m 09 09 c LO cq3 0 0 0 0N (N 0 0 (NN (N ( 0 0 1X, o z 0Lr= \o o 0 0 0 0 0 04 (N (N m - N)Y 0 0 C0C C C zz WO 2011/015241 PCT/EP2009/060168 381 A 0 0 0 0 0 0 0 + N 0O (Y) m' LO 09 0 0 C9 co) -H 9' 0 09 -- H C'J 009)C 4.3 CD 0)) CD m' H 0 0 0l o0 Q0QQ0 LO 0 LO 0 ~ 0N 0 0 00 0 (Do o Q0 Q0 0 0 o o N) m0n()N( c c cc c 0 C' 0~ 1~ :)1 C C'J -0 LO W r- co0 ODO O DODO WO 2011/015241 PCT/EP2009/060168 382 m 0 z A , P 0 0 0 0 0 0 co w ) 0 -) LO) 09v >1 r-0> 9 -09 090 0 9 90 .H 0 vHLO) Nv 09 09 Nl 000 0a0L Q0 0 0 z LO 09 09 0 09 0 00 0 0 0 0 C9 - C- 09 N9 C0 0o 0)Cl0 0 LI) 0 0> C 0 C C 0 0 0 0 0 1 0 N CY L 0 C'J (N ( cqJ c'J N z WO 2011/015241 PCT/EP2009/060168 383 o I 1 I I N 4 I OA 0 I d VO 0 4 ) r d 42 H r- H - I 4 C , d O 0 I I (N I d 0 C 0 4 0 Cd C I C - 0 Cd r 4 -r- N a) 0 ) t -r- 4Q - I C CD -- N -- I CD I A-| CO _ I o 0 -- 1() COC v 6 0 I M O0 - 0 d 5 4 (N -H v-1 4 '' - tO - I I - r-, '- -, 0 r 0 O O r -1 I - I N r- >so - 1 0 r-1 1 4 G) C - - C I v v, - I -- - O -1 r- -1 1 0 - - O r-1 vO N I v-| - 2 - (N - C - N C N C I CO I - H - - CO 0 i ) Q) 0 L r-| (N 03 N rd L C Hv - 1 - v H 2 42 0 4 -H (N r-I r- r-I H- - I 5 - I O - | 4 -)0 0 o 0 4- 3 LO rlnO O -P q) 42- vH v0 4-) 0S 4 -H I 0 -H 0- 0 - 0 |: O M , 'O CrI M 03i - l N -Q 1 n co I O q) q -I rI N 4 0 - 1 H N 0 I N q)N S HO N 1 -o o u 0 d -H I Cd 4 v-I vr-I v r rd -vO H- - Cd 42 I r OC ON 001 0 0 C So f) v- v- 0 v- C- -H 0 O 2 0 H 42 a) - C - H 4rI a v 0 ) 4J Q | 4 -1 CO - CO I I I H- S I 0s rd - - - 2 0 rd L0 - C -H Cd 0 4 v- S I 0 m ) vH vH 5 vH 0 if ) a) o N - rd OH I H - rd - I N N 4 a) - ,4 Cd CO ) 0 , r mr 0 2 A S -H 0 H- 0 (N A N A N A t
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m - rd H I H - C rd I 0 H L H1 d U - H O - I 0O H U O r- 4-, mI a1 ) U) 4-, 1 0 . 1 ( . H L 0 4-) 0 0- - ) H CO -I vS -I v 0 H 0 H0 I H |H I H A H , 'M| o a 1 -- 1 -1-o) 1 r-1 r- - O 1- 4J - I I - N - N - I I - OCO C CO p r) rd CO o 42 r) 42 rU rd CO U) 0 - Hr O CO N v-S C rd 0 Cd CO N v-1 0 -H L0 L0 - vH 0 I vH N N 0 I - vH vH S | C - rd rf) Cd - I C q ) - ' ' r) (N a U rd N Cd r (N if --- 0 0 0 T 0 I H 0 N N 0 I -H - Hr I H O- 0 0 4 - 0 N - 0 5 4 i) I f U N 4 I 0 1 ) > C N 0 I 0 4 ) 0 4 0 N 0 I o 0 0 CO 0 C - - H 0 - I 42 2 -H 0 rd H -H rd - N r-v '- 03 (d H 03 Cd '-' N r-1 H- 0 N - N [ | 42 - I H 5 >1 H 5 I 42 - >10 42T U) O I I > U) - C 42 - rd 2) I > 42 C. d 0 Cd N 0 vH 04A 004 0 vH Cd U N - N U) N~ Hr vS -toSN4vSNHv m C )C >1 -v-v 1 ( C I - rd >1 -- 1 >1 Cd N' Cd > N (N v N v 0 4 S 0 N (N v 2 C N N C H C r- ( C v- - N v- - C v- N N ) 4 42 if) X - - i) -H (I - H if - 04A if I O04 UI2N CO, L) E -- WO 2011/015241 PCT/EP2009/060168 384 I I | I || kO~- 0>( I v-H v- -H In I a - - ) - ~ I > 0> ' (N H 0 C - vH -H -H A Id C a) - F - - 5 .r- .- LI> LI> r) S- rd N r-I vH N I - .Q a) H v-H -- A- (NI- El r I A - v-- H V >1 -- rd >1 > A r I A - a) (N AH 0 0 A 1N - 1 1 4 I I - C - o I o a) A A a) OH I -, I A S1 .10 41 A a) AIt A> H 0 I I C N >1 N >1 t ( (N C ( 0 I 0 I 0 I -A- '-' - A 0 1 | 0 I 0 A LI> C |L I ( A a) I C I - I C I C I C .H (D cO O H OO O H O 1 - V 0) Q4 A) 04 a1 ) 0 C) A A- I- -A- | | N -A- N -A- '- A- A- o 0 i 0 a) 0 -l 0 Nl I l 2 N V N U) -H V - V N V -, O9 0 I 0 0 Il I Nl I '-I 0 - Ar- > -A- C V 0> V > - o> C A N - l -H I - I A I A A V - - V C) M9- 0 - 09 -) U m I [ I a) A- H I OH I OH rd) 0 I A- 0 V A r- - 1 A O I A r I > r-1 - r-1 - N o4> H - AAr-1 --- r- Aa) >1 I A I | >1 | >1 | 0 A-I -5 >v - U) >1 - VO U) V - o d ol H rd.- 1 o H - .1 - ..- 0 --- ..- M rd .
>1 N V 0 0 Vo LI (U 0 a) 0 ZNC 0 | N0 SN C 0 t C ''t C C N C A 0 -n A 0 a -H A I a) I ) I 0 a 0 It F t' I V t' C LI> LI V A- | t Ql r I N - I >1 A A > , (N C V C LI> LV -H o rdo r- ,) - H r- - a # ~ A C> N A A o A l 0 A 01 A A O A A- 0 I - I N C - ) C t F I - r- - ~ a) CI - ~ ad -r I > t A -r I I md 1 (N LI> >10 - - 09 a - -r- S LO r, A- C mI A- L> 10 N a) LI> rdI LI> A- r LI -. - r-I >1 A- A- V I A- a) I A- - >1 A- 0) I r- - - V O O O V O r-1A O -r I 0 I 0 C A 0 I I A- C I A- I C A o - a) C - o C a) C - r C a) 09 I I 09 - >10 A - 09 >1 0 9 >1 0 9 >1 V > It 0-, A C- 0 9e - 0 > C Ae- > C) (O ne C 0 A- N Hn - >1 -HA - L> V A- -H >1 A- -H A- >1 -H C O >1 '' C Nl A- r- t ( - Nl C - Nl - C Nl a) 09 I I I -r- V I - S 9 V -r- 9 V 09 -r- V 09 (N > 0 t d It -1 A It 09 a) t rd a)-09 a) A | r-I -H N A- V. - N -H - N - -H N >1 O9 I A- A r I t A- - N1 09 It A- ra 09 H It VQ C >10 Itr >10 Itc e It 0 e a) 09 0 It V -- O 0 N N1 Nl N I C N- Nl El - Nl -- Nl Nl V A- - -H C Ni V C a) -, '-- V Ni '-- V '-' N V 01 I N Nl a) >1 a) 0 N A- I a) >1 I 0) I >1 a) r) 9 V V VQ 01V VQ 0 >10 V 0109 V 09 01 C rZ rr OC 0 N10 WO 2011/015241 PCT/EP2009/060168 385 I r |(1) 0 Hr-I N I -H H 4-0 ) (N - I r-I rd o (0- (N I I 0 H0 H I0 10 N 0 1 - O C(N ( rd- r- Cv, 0 N~Y I1 (N(1v-)0 N4 o If 5=4i H- - 1 0 I -H 0 - 4-, 5 0 0> I 4 O, So H- H >1 1 0 4-) 0- )1 4- I |k - 5 >1 r 1 H 4 - T 4- -- O rI C | 5 rI .5 > 4) 0 I . -' -1 - 0 - - I 0 - - - - I rI0 H I rI I -r > I H N H O H O N C0 H 4- - -C, -I 0 o > CD Q) 4 -) (0 0 D r- |5rIiC r - >1 rI H rd Cr r O . 0 I H' 0 [I H M O O I H 00>, - N 0> N 0 Og L> O -H- N 0 -O - O nH - - O - -H 0 O H r1 U n M M0 I 0 O V0 0 M L0 Nr 4) H I H 4- H- -- - N -- | r-) H ->- nI - H I 4J H1 -C -> M - H H H | 0> H I I H 0 > H -I Hn >, Hd Hn 0 H, v-- a]( 0 H H 0 (N 1 U - 1 -i a -l 1 - X I -5l =N - a - N H H9 r 09 0 04 r0 0 - 1 ) H (N 09 H0 H ) H I |- H H |0 H oO o> N O > o 0 v- M NH N> oNO H 0 4 - I 0 - rI 0 ) I U 0rI 0 ) Q (d -r- e d -r-| -z 0 d - 0- CO XM d - >1 I .0 H- I .0 H- I 0 H- 0d >1 n H- r I | - , > N - > >1 N . '- '-t > .N a 4y I " .0, I o , I C" .0 4y 4y O -H .0 I o 4) 4J 0 - 4 ) 4 .. -P 4 ) 4) O nH S- 0 - 0 00 0 00- Z) | -4-| > 0 Z 00 H 0 S 0 |0 d I HL l S r t - LO - r-H t rd () H H LH rI r-I t >1 t- >1 r- ( t v- r) rI N H t >1 r r- D '- I O( - D ) I O C' rI r- t 0 rI O0 I 0 C t H-1 0 O H 4- 0O 4 H H 0 I rd , H-1 C 0 -- C n -H I O H 0 | C H C I - -, N C I 0 H 0n (0 C) C - 0C) OQ - rd C) r0 -09 0 n V N - Oa O) M0 - >10 0d - >10 09 - >1 -, r I 0(0O 4 0 09 0 >1 H- H- C) (0 H- ) Nl (0 n- ) H- (0 rd Qa H- V (0C 5l C - >1 -H C) H- >1 H Q, H- >1 H >1 r- N r- - I 0 H- Q, -H 0n 0 N -H - 0 E N - - 0 Nl 0 - C H- rn 03 - - Ni 0> -r- V 0 09 -r- V H- 09 -H V -r- rn I >1 0> a ~, 09 H- V - t rm 00> '0r >1 0 '- 0d t- 0 N I - - 0 0> >10 09 -5 N 0d - -5 N 0 - -H N -H - I 0 0 L> 0 - 0 N r- H d rn 0 -9 -H rn H9 -rn 0 I H -H rn -H r0 -- O r 0 0 0 r0 tO 0 0d 0 0 N 0 -- - S 0 t r0 i O- N V C N '-' N V Ni - H -H - H S- - 0 V I >14) N I >14) >1 I >14) >1 I Nl Nl I - H- I >14) 0s OV CO2 DV 00p 2 V 0D V V 009 >10 2 V z1 ' zT 1z 'z1 z1 in0 ojo 0 La O N0 L7 0 0 N N NNNN WO 2011/015241 PCT/EP2009/060168 386 03 09 - 0 I A| r O o L0 SO H I0 > H -- o r-H C - N H H - H . C - H H NI N 0 0d C H- | | 09 | S1-, 0 - (N N | H H 0. H ,C I I I 0 I - a I - - 0 rd C rd OH -) 5 O >1 ~ 1 1 (0 o I (90 0 I I S G) rd 0 Id I 0 0 (d 5 5 | | H - (N I I | C- H- C H 0 H - I H C H 0 4-) -- 0 >1 0 -- 1 >1 V 4 VC I C - H N -I H ) - -, n $ -, 0 N 2 O 0 N N 00 (9 4d 4- HH 24) 9 .o -A 0 N I - I 0O - 0 I 03 0 O 03 I 09 H - r 0 - C H | D 0 H- H i >1 C H - | (9 0 H - >1 - VC | U N >1 H u 4-) 0 4 0 o I -- - 0 I H - m N 09 - I - 0 N -> VL Lm 0.L ,OH - H - H -r- r '- ' * -r| r r- ( '-- C ' 4-) L1 r C O i O V H I N I V H -0 0 N | I 0 Cd H H n H 0 M t~ -- I O Hr I | | d >1 | O | >1 -H I >1 ' H- H- rd r-- l V rd H- H- rd | (9 S (N 9 -r - 1 - 1242 N- i N (N- d o O9 U V 0 Z0o 0 N C - 0d H H I (94242 0 5 (9 H I O9 - -l- (d I -l - ( - I 42 -r- -H | d 4- 0 N (9 09 N 0 50 0 t 0 N C 0 N 0 I N H I 0 0 H H 0 I 0 U 0 0 Ir N H N 0 H I . ' - Lo H | ,. H d 0 > 1 Nd C ,C I L0H k I -oNV | >1 ,1 N VH V) H 0 4-) N -1- V4-V)2 H 2 42 4 42 -1 m 1 H i - 0C H C 42 - 42 0 > 0 00 - H ( H O 0 0 042 C S-J V S C H H- r -1 '- S C - S I -H- -H- I O -H- H- -iH H - H 0 H -H- -H- H -H- 09 t0 t 09 N -t S - i o >, C t - S t - H H I H- O I 0 0 .- I I - 0 I 0 0 - N L9 - | L9 -, e rd 0 0L rL LO 1 H- L9 0 H H L9 0 H (0 L9 H H 09 H H 0.i - H- | - >1 i H I I H4 0 - >1H 0 - - I H - - 42 '- - C 0 - t H - t H H 5 H -I H 0 r-1 o O - r-D- rI r- - H 0 0z 090 0 H 0 . 0 0 . I (9 H I -H I H S I ( H S - I -- -H - ( 9 - 0 N -- , ( 0 -, r (9 - 0 9 0 0 o U2 - >109 N 42 0 >14 09o -- , >14 -13 9 | | 0 I (0 O Hr- (9 0 0 I 0 (9 0 O Hr- (9 0 0 rd H - rd '-, H- >1 -H -- H 09 H- -H (9 H- >1H (9 H- N H - N H - C N N H - N 0 - C N 0 - O >1 U2 0 >1 U2 -r- -4- I 2 - 09 -4- -- , 9 -r- 42 -- s 0 I I 0 I I 0 '- rd 0. I| 0 rd H- 0 t- rd H- 0 N 0 -0 0 - -H N 0 H- - N >1 - -H N >1 - I H- 09) | H U9 H Nd H H - 09 Nd ,V 09 H r Cd U O9 I 0 0 I O 0d >1 - - 0 N 4 0 0 re 420 N C - N C -- N N N 0 -H - N VC - N N VC - 0 0 0-- 0 N- 42 C H 0 '-- 0. '-- 4 0. '-- -H - - -H -H I >10 0 - - I 0 ( I >1 0 N N I N N zz 'z 'z 'z -J )=a az /\ /\/\/\ / /\ /\/\/\/ O 5- L OzN NZ WO 2011/015241 PCT/EP2009/060168 387 Ho - LO H- 02 G I H 00 5 0 4-) H (4 0 0 ) u~ (U J > 0 Z (0~~ C) H - - GD~L 0>I r H H~ I ~0 0< >1 N4 C) 0 ( 4 LC C-1 ->1 L4] GD H~-C N D>1G 4-) 4-) U I~- GDx~ )4) G CN (d G d 3 I GD 32 dl 2>5 GD 4-) H Z t OH D .5 0 I - r -I z H H N3N )I - I a) 0 I r H H N4-) C) h -0> x rd 4-) I I 4) 0g (O 00 ( 00 GD I N0 l 0<~~ >ii N d U c O) D 0 0 NW N to GD) 0) 0 0)0 0) GD N(Y Y z o o 7 77 WO 2011/015241 PCT/EP2009/060168 388 -P oW op op o OL 0 rd CH Vd 0 0 ofl ~~r-H O .. I -H -4-, -C L LH 4-H- - |1-1 ( 04] I, ,U u 0 - I o-- q 0 0 tp 4j 7 -J -i 01 H H r ~ (U 5r 0~- -P C e ( 0 (U 0 00 1N U) c z ~ Z CC4 00 H~ >O (-5d z n) 4) a) H H HC O O O O0 b) _ -r 1 0 11 (U ( H 0 )C 2 C ®t CC) (U0 (U (N 00) H 0 0 H OH 0 Y m ) IY H H (Nz WO 2011/015241 PCT/EP2009/060168 389 H H .0 0 0 0 0 10 U) 0N 0 >1 H( ). CV ( V)(N H 0 Co a) H H ( o0 .0 - (t 5 0 Q4 0) (N) 0P4 0 0 0 0 Qww Q (D4 (d) 75) HH 2 -1H a ) a) 1 p4 0 V. 0 Q 93 d0 0 (9 . .0l - 0 > 0 0 4 4-) CY) CY 0Y _ r _ H 09 Ci (9 ~ 0 ~ 42 H 0 a) 2 H Hz m Hz 00 ~ H00. a): 0(9 4j U 9 oC~4i~~ .0am > 0 0 -1 i 0~ Hv (9 C) z -C0 WO 2011/015241 PCT/EP2009/060168 390 to 0 L c 0 0 0 0 0 0 4-) 4-) 4-) 4-) I~~:I 0 )U 0( ) E0) 0 Ln 0O N I-- Cn)9 O - LO r-) C0 L n LO LC o c.oi-iu o- 4-) Cz z0 Q) 00 En ) CD H p 4 -O -O Lz 0 03 E-1 C) 0 O O OO 0 Qo 0 0 En En 0 0 0 ~ ~ ~ ~ - Hc0LE N(N( (Y oo C0 LO () EDED o- 0 IZ 0 F,() =Z Z Z Z= U (N 0> ED 09 EDE - mEn 0 En 0 0 a) 0m0 >)C)CY Y r z CN WO 2011/015241 PCT/EP2009/060168 391 m 0 7 -P 000 0 0 0 +O C) (n 090 0 00 CN- I-- C09- 09 0 0 0 0O Cv- 09 Cv 0 z 0 04 0 nQ0 0 0D C- (n- Y") 09Cn 0 09 uv 09 uv 09 zz 0 0 0 0 00 0 /Y v r r Y z~ WO 2011/015241 PCT/EP2009/060168 392 0 -) 0 0 I rd \N r-1 0 N N (N - - 0 I 0 SI (N H .5- 0 H O 0 ( H I 0 N (N I 0 0 -- I I O o .-* (N - 0 > N H r | 0 > 0 r-)0 0 \ 0 o H 0O -0 > - V I( H cx] - -A I _|_ I I -o - >L rc S - 0 - 0 r0 .- | H i . -i j 0 H H - ( t - H 0 S o O - 0 r0 i >10 rd5 e0 Hi I H D r-1 .4 a -- ) N W Nd c rd9 0 c V 1 0 o 0 I H W V- 0 H-- (No t u N H 1 o N o1 o = |0 o10 H~~~: 4 ® V 0 . H4O H Q V -H H - 0 H V I - (U - - N 0 0 , N I - - H I S N 0 0 0- O H 0 n I 0 H 0 .C 'o r- .C N |, . - (x] N 9i.0 0 S o H, 5 H - 4 - 0 H V md r- O r- I co d |O -A o (N -, O H 0 x >10 I A V v H o 4 H 0 -A 0 0 r 0 0 q) ) 0 V- -H 'I H 0 0 o S > i - cH] 0 O . I i 0 r 0 -P O 1 0 q) u - N T Z - _Q N -Pl 0 - I r- -P -- (-d Y) -r- - N r-I - ro C0 z 4 0 (0 Vn 0 Q0 0 t n z V - 4 I N (N 0 0 - k H . O 4 r O -0 -- 0 Q0 5 H 0 V H (I) H - A V H H 0 0) 04 0 ( 0 Y) r V M - a I-- O - H rH I -1 HO dLO rd _Q | ( u co C L - r-| co Q N V r- 0 00 L HH > 0 0 - r-| 0 OH d V 0 I 0 C - 0A 1 V I N Q0 0 u I N 0 V N (4 0 0 V H GD - 0 I - 0 1 - A 0 - L no ) V- 0 0 N - - -I 0 - m r -A H r m m 0 I H I I d -H 4- H -i > 4, r H -H (.4 0 - N V r- H I - 4 - I 0 I 1 0 V 0 0 0 0 N UM I 0, 0 V Q UN O 0 ! 00 0 0 - ) O U | - -0 0 -| 0 - 4 H N 0 M 0 4 -5 4- 0 0~ 4 04 0 - 0 M -5 S 00 L0 V O H O H r-H - I LO r-OH I VH c O r- - I ' V N - - >0 0 ] -- H > 0 o0 c0 V 0- 0d 0- H H I 0a 0- - H H 0 r0 |H N( N V. I> 0 5 o (N Io 0 0 5 . H - - I 0 $ 1 - H -) >1 rN -A - 4 >1 0 0 0 0O -- I ) 0 . - -I - O .|d I V L [1 0 I (N 0 r-1 0- I (N 0 0 0- c(] H > 0 0d 0 0 I 0 -I - I | V 0r| L I V - - N o e1 1oO - -I ra0 0- - o ~ - V - rV Va I- 0 0 H H H 0 0 0 H (N 0 0 0 0 0 I -0o - o > V 5 0 H - >1 5 V 5 0 H o N (N OH H 0 V H 0 OHs -0 V H 0 OH r- 0 x -rI Hs -Hr 0 0 i >1 ,NV -O Hcs 2 i > , NV - 0 >1 N 0-- 0 0 I -V- 0 0- 0 0 --- I V 0 0- 0 - 0 N 00 - I V V '0 0 >0 - Nor- V V 0 - H V rd 0 O- 0O O WHO H LOO 00 0 -z O OO 00 az =Z= Z= cc - \ E--I 0z 0z 0rz Or co Yzzo Nz 0 \zzON\zz m m a) 0 04 0l l nmc WO 2011/015241 PCT/EP2009/060168 393 rG LN LO d L 1 O( 0 I0 | | o~ ~ w d D d C C d -- C (N C i rd Cd i o i d 0C C H CD i C ,O O I) H l - . I o 4 -o >1 O d 0 d I I d c D X Cd N N D N-| - ) O - 1 >1 0 - 0 1 0 -i N -ri G) G) - o & ( H ~ Cd 4-) N <- 24 A1 4-) 00 H- v- -- 1 4 4 00>1 I II v-I S \ N N H 4 H - H-1 H~c -0 cc) (N 4 Co ( >1 I - --- - - - - * H H H-N |N H I ( H4 - | O I L L LO~ -- (N- r0 -- N N (N e -r- 0 r-- N -A 04 H H H H 4 I r- 0 r- '-' - N -' 'O 01 ' '-' I (N N 1 ) (N H -H -P > ) 1 H IH 'O 0 '~ I C H I 5 o 0 5 i H '- -H 4) P -H1 4-) r .H1 1 4-) - H -1 Q0 e >1 O rd -) ( I ( ( H rd H o ( 4 H reN H O , (N t r N 4- >1 ) >1 rG O >1 H 0 H I r2 O I H 4WI Or 4 Cdt 4 I N N oN O Cdt KO I N 1 -- Ho C 5 N C S - 0 C dv-- 0 H N Cl H 0 '2 0l Cd H Cd Cd H A 0 cv-- > 0 d > H (N 4- Cd Q00 Lo Cd 0 1 H d - 1 d I7 CD 0 v-v H 0 4 4 0 4 4 - O N '-, . ,-, to - I Cd 4 i rd o C i Cd H i i H o Cd 0 4- Ct 4 Cd C0 4 ) HH 4) Cd m1 Cd C iv H- 42 (N C (N L C | - | CO (N (N Cd |I - H- ( N H I C 0 (N 7 - N H - m N H N I H - I H Cd O C I O 0 - I 0 Nd O H- Cd Cd - LO d - 0 - -H- 0 - C LO C C 0 |I ( Cd | H- C | | o S N o -5 H C -- | a) N 4 C 0 - Q4 0W N Cd 4-) S - 4- - Nj 0 42 r H Cd I I 0 H-nH Cd H rd rd I C Cd I 4n r H 42 r - - >1 N - H H r| - -a Q N > - C >10 (N 42 (N > - C >10 N E~~ 0 o Cd (N 04 I 0 -H (N C01 (N T I 0 <4-n ( HI (N I C rd I C N - v - d rd I Cd >1 (N S Cd N S rd ( -5 -( S Cd N S rd (N 4 (N (N -H 0 (N -H -,H '- (N H -H 0 (N -H -,H 42 H- t '- I s - - '- r-I '-' '-t I - t - 'd - -v (N H-1 I >10O I 0 N - >10 -H H- (N (N I (N (N 0 H- (N (N H- I I (N I 0 H T H - H - - C 0 '--' | 0 N - T ( C 0 - (0 - Or - >1 >1 - 0 ( -' rd >1 o II (N v H O -H H 0<0 | - 0 I O H I 0<0 (N I - H- -H - v- 0 rd (N >1 d 0< -H - 0< 0 Cd I 4d - | - I N N I N I -, I N N - (N - d ( - D <4 C -4242 Cd - Cd (O -<42 C 0 0 (N O H- (N U)--s Cdt- U d Cdt- U) H- (N U)--s C ' Ln | '- L 1 (N H - H 5 N 42 L 1 N- LO m 4 -H H- (No H 0 C H >1 r7 H m -1 0 o -1 >1 Cd 5 - I r--I - C H- - C N Cd - >1 N Cd - C H- - C N Cd CO - O rd - U) -- rd c o ,C Cd c o r d - o -n Cd C N - ( 4- -, M rd 0 -) ( d 0 4-N - (N '0 M 0 - 0 (N - C LN - H Nl -Q C N . - C L - -H N Q e - -N co Cd m o Ni 2 Ni 04 - N U ok ( N N 1 - 0 0 -- o >1 CD rd o rUd Crd o 0<--- o >1 CU - v -- H -| 4 0 C 4 0--- -- | 4 $4 0 mz - zT z: LO IN -z 0 0Z 0 Cl C Cl) ClC) z WO 2011/015241 PCT/EP2009/060168 394 L L C C -, C 0O GD 0 GD C rd C rD .5-| $4 $4 H I I > ) O D N N 0 I - GD -4 o I dI I N I | 0 0 N 0 Io r-I I O GD N0 Y- - rd r, 03 0 00 4-) - H G 4 O~ | A GDO I) A -4) GD - | I H H - O H C 1 A 0 ' 5 o A N I N O H I -0CD H 0 - Co O I 03 r I N Ard a pD >0 (Ii r- I1 N -r- HA-> A1 GD-I O 0 -I o O H - O< G A G A I -W U I N G - N o aHO O9 -D | CH 0 o i Co > co N -C > 0 4-) H5 4-) X~ G GD) 0 D G 0 - 0 4 - 7 I - r- A >1 D o i o r-0 N O H >9 4-) 1 C- I H 0 A > 9 GD A A N A GD N0 -- A 0 (5 GD N O GD G D 0-1 -I GD H rd A ~, A - I- > L >9N P | N I P N Z H r- GD ' r-I > ' I >1 GD - 0 GD H 9 5 N I 0 0 5 A 0 CD OA G > -,-C q) Ili O O o S -, - -- H LP H 4- I 0d 4- A 0 4 A 4 I GD D I - H __ _ _ _ N a0 Nd ' N H rd>9 r I rd H _ _ I >9 I A-1 I GD( I 4) 0 GD G D t -1 GD G Dt0 -z -z \ z / GD / N GD O 4 m~ 0 0 D 00m- _ _ _ _ 0 0~ 4 P 0 -l OD 0) Gd GD GD 0 A GD GD Cn 4- 0, -n A P 4 H 0 N Q0 / 0 0 O0 U) 14 = wO - U M LOO o H x 14 0 0= WO 2011/015241 PCT/EP2009/060168 395 Ln) I O H U) H D a) 4-) ) I w r , C) (D Q) cD N Q4 G o 3 U 4J 0 N0 (?j -Q N T C0 a) CC UH Q 0 )0 0 I0 C)0 0 N N C) .0 *H mD C N D I H C H0 ~ U) I G G C G H CC H GD HO WO 2011/015241 PCT/EP2009/060168 396 Scheme 1 Building Blocks Type A OH CMc OH A020, H2SOA N cM C0 2 H AC 2 O, NaCH NN C0 2 H F -C02H F C0 2 HN 12 7 8 OAt
CO
2 Ha
C
2 H
NH
2 NHBoe 3 4OH COHOH CO commercially available commercially available 1 OH OAt SH SAc N AC 2 0 A 2 O. NaOH N 00 2 H- N C0 2 H C0 2 H :C2 5 6 1112 Scheme 2 Building Blocks of Type B *NHBoc *NHR HCI-dioxane H SN N R Alloc AllocOSu, 13 R = H TeocONp, 15R H(HCI-salt)
CHCI
2 14 R =Allot Et 3 N, CH 2 C1 2 L- 1 =To NHBoc HC-i). -NHR R Alloc AllocCl, CH 2
CI
2 , 17 R = Hl TeocONp, 19 R =H (HCI-salt) NaHCO 3 , H 2 0 __ 18 R =Alloc Et 3 N, CH 2 Ck2 20 R = Teoc BOc BOG I AllocCi, CH 2 CI2,I NNaHCO 3 , H 2 0 O N SN N'N H Alloc 5 21 22 WO 2011/015241 PCT/EP2009/060168 397 Scheme 3 Building Blocks of Type C: 0 2 N 4-nitrobenzene- 0 1. BnBr, NaHCO, sulfonyl chloride, 1.cHN,, I BnMr, NHO Hpyridine, CH2Cl2 BocHIN COAl DMC-ioae HCI H 2
N...CO
2 All HN..NCO 2 All
CO
2 H 2. HCCdioxane CO 2 Bn CO 2 Bn 23 24 25 CH3), DMF, DBU 0 2 N O 0 H 1. thiophenol, HCIN.. CO 2 All Cs 2
CO
3 , CHCN
CO
2 Bn 2. HCI-dioxane CO 2 Bn 27-HCI 26 , 00A 5 steps H C2 BocHN,, C 2 Al HCI N,,. CO 2 All
CO
2 H
CO
2 Bn 28 29-HCI Scheme 3, cont. Building Blocks of Type C: OH DEAD, HCI HN' allyl alcohol, HIH CbzHN PPh3 [ CH 3 NHSi(CH 3
)
3 CbzHN -? SOCo2 CbzHN
CO
2 H CbzHNCO CO2H CO2AII 30 - 31-HCI 32-HCI
NH
2 4 steps, HCI HN CbzHN - see below CbzHN CO2H CO2All Cbz-L-DapOH 32-HCI NH2 allyl alcohol, NH2 -p-TsOH 1. CH2Cl2, NHNs CbzHN,, p-TsOH, benzene CbzHN,, aq. NaHCO 3 CbzHN,,
CO
2 H CO 2 AII 2. 4-nitrophenyl- CO 2 AII Cbz-D-DapOH 33 sulfonyl chloride, 34 pyridine, CH 2
C
2
CH
3 1, DMF, DBU HCI HN 1. thiophenol, N'Ns CbzHN,, K 2
CO
3 , DMF CbzHN,,
CO
2 AII 2. HCI-dioxane CO 2 AII 5 36 HCI 35 WO 2011/015241 PCT/EP2009/060168 398 Scheme 3. cont. Building Blocks of Type C:
H
2
NH
2 N CF, -* PFo Ph9) 4 , N allyl alcohol, 1. CFCO 2 ,E. Et 3 N, < morpholine, THF N ~ CbzHN P-TsOH, benzene CbzHNJ MOH. CH 2 C12 CbzHN o_, 2. conc. aq. NH 2 CbzHN 001C0 2 AII 2. CH 3 I, K 0O 3 , CO2AlI 3. allyl alcohol, C0 2 AII 37 38 DMF 39 SO1 40 HCI
NH
2 P-TsOH - CF, 1. PdhFPhj)4, 1N O 2NH- 2 ~N 0 morpholirto, THF N C aiiy alcohol, 1. CF 2
.CO
2 FI rt 3 N, 2. LIOH. H 2 0. THF: CbzHN p-TsOH, benzene - hlN-T eOH, CH 2
CI
2 bzNthenl aq. HCI CbzH-N~r COH CO 2 AiI 2.C31 2IF M I 3. allyl alcohol, COAI 41 42 4344 HO Scheme 3. cant. Building Blocks of Type C: H 0 allyl alcohol, psH 0 .IN ~'a'OH p-TSOH, benzene 'N N--- OAI 45 46 H O AllocCI, 0 N L 0 H NaOHH20Alloc' N -OH 45 47 0 AllocCl, 0 N -'O'H NaOH, H 2 0N H 48 Alloc 4 0 CbzOSu, dioxan, 0
H
2 ()Na 2
CO
3 , H 2 0O OHCbZ' N " OH 550 51 WO 2011/015241 PCT/EP2009/060168 399 A-cl Fragments Scheme 4 CICOCOCI, OAc cat. DMF. OAc 27-HCI, i-Pr 2 NEt, OR
FCH
2
CI
2 ' THF I I O H F COCI F N C OAI 2 520 0B (CH N(CH 2
)NH
2 , - 53 R =Ac THE 54R=H CICOCOCI, OAc cat. DMF, Oc 29 HCI, i-Pr2NEt, O
CH
2 01IO~ THF OR F 2O~ F COCIF 2 520 0B (GH )N(CH 2
)ONH
2 , rn SSP Ac THE 5 R-IH QAc CICOCOCI, OAc 32 HCI, OR C0 2 AII cat. DMF, 2,46-collidine,(S Et 2 O CH2CI, PiNHtCbz
CO
2 H mGCI N 3 57 0
(CHC),N(CH)SNH
2 , rn :58 R = Ac THF 5 SR- 1 QAc CICOCOCI' ~ 6HI OR C0 2 AII ct M ,2.4,6-collidine 14 N. Et2O N. CHCl, N. NHCbz COH 6 ,Gk. 3 57 0 (CH3) 2
N(CH
2 )3NH 2 , rn S R=Ac THE 1R WO 2011/015241 PCT/EP2009/060168 400 A-cl Fragments Scheme 4, cont. OAc CICOCOCI, OAC OR t. IDMF, 40-HCI, i-PrNEt. rcCO2II N. CH 2 C1 2 THF iN K
CO
2 H a coci t rN NHb 3 57 0 (CH3)N(CH) 3
NH
2 , 62= THF L.. 63 R =H COAI QAc CICOCOCI, QAc OR NHCbz at. DMF, 44 HCI, i-Pr 2 NEt,
CH
2
CI
2 THFN dCO 2 H Cob COIN 3 57 0
(CH
3 )2N(CHA)NH-,, 64 R = Ac THF 65R=H AcCO N. at DMF, 27-HCI. i-Pr2NEt R
~C
2 H 0H 2 01 2 AcOO N. c THF IO"r ' 4 66 0 002Bn (CH )2N(CH 2
)
3
NH
2 . 67 R = Ac THF F - 68 R = H OAc 01000001. OAc OR CO,AI ct. DMF 32 HOI, i-Pr 2 NEt, CHC1 3 N. THF NHCbz N N OCIN- N, C0 2 H co 6 69 0 (OH3) 2
N(CH
2
),NH
2 , 70 R=Ac THE 71 R=H WO 2011/015241 PCT/EP2009/060168 401 A-cl Fragments Scheme 4, cont. 32HCI, HATU, HOAt, N ,-Pr 2 NEt, DMF 03NHBoc NHBoc/ OH COHOH h ,N CO 2 A 10 72 NHCbz CAc CICOCOCI, OAc 27 HCI, i-Pr 2 NEt, OR 0 CO 2 B3n N, C0 2 H CH 2
CI
2 N ,N COCI THIF N , N - O I 873 (CH)N(CH2)NH2 74 R -Ac THIF 75 R=H OAc CIOOI OAc CH 3
NHCH
2 CH=CH OR cat.DMF, 2,4.6-collidine, NEt 2 0 CH 2
CI
2 N C0 2 H - OC coc
N
0 3 57(CH 3
)
2
N(CH
2
)
3
NH
2 , 76 R - Ac THF 77 R =H SAc CICOCOCI, SAc 27 HCI, i-Pr 2 NEt, SIR Cat.DMF. 'THIF CHC1 3 ______N
-~CO
2 H cocI IN NNC 2 AII O CO 2 Bn 12 78 (CH 3 )2N(CH 2
)
3
NH
2 , 79 R - Ac THEF 80 R =H c2-13 Fragments Scheme 5 NH~oc 47,N]o lio Ho 2.4,6-collidine 51~cN~o iHo HQ ( INHTDMF Ho I H NJ Z 24,6-collidiie I HO HAU, HN..L 7 HCI HATU, DMF HON.NH H & N 'lo.H N,(b 13 81 13 HCI 86 1. 47, HCTU, N~cHo .4.HTJ Ho 8CT NHBoc CI-HiClt, i-Pr 2 NEt, INBCNHBc14.HT,,Ho HODMF CI-HOBt. i-Pr21N1t, HO,' N H__11____S__ HO HCI 2. LiOH H2 0 01 CN I N DMF HO N N
H
2 0. THIF O NA, HCI 2. LiOH-H 2 0 171HC 82 lo HH0 THE 1 C8217-Hol H2,I 86 Allot B-c 1.47, HCTU Ro IN CI-HO~t, i-Pr 2 NDt. DMF HO _N) H HI 2. LiOH H 2 0 O ' I o HI H 2 0, THEF-- 'lo 5 83 1 ICI8 WO 2011/015241 PCT/EP2009/060168 402 Core 01 Scheme 6 NHTeoc NHTeoc NHTeoc: OHl1 l0 T31P. CHC1 2 , 0" OH CO~I 18 I i-PrNEI t ~ FN N ADOFP, PphZ, CHC1 3 FF ~~c'~ O CO 2 Bin 0 CO 2 6n 0 CO 2 Bn 54Pd(PPh 3
)
4 , 1,3-dimelhyl- 87 R' = All1, R 2 = Al 1.G Ex.1 barbiteric acid, CH, 2
CI
2 fEtOAc 88 RI = p2= H Core 03 Scheme 7 NHBoc YHBoc NHR' N N-Alloc NR2N / OH C0 2 AII 81 3. FDPP, DMF F-0; N ~~~DEAD, FPh 3 , benzene F-a ,-C2' - F - N O CO 2 Bn 0 CO 2 Bn 0) CO 2 R1 54 d(~h)4 13-imth1-89 R1 = All, R = Alloc H 2 Pd(OH)2-C Ex.3 R 1 = Bn, R 2 =BOG barbituric acid, CH 2
CI,
2 /tOAc 2MeCH, THF2 90R'=R =H LEx.4 R=H,R = BOG HCI Ex.5 R 1 =Bn, R 2 H - ixn Core 04 Scheme 8 NHBcc NHBoc NHBc H-'N Alloc IN '63P C N- j N-R 2 T3,C2C2N 0 NOH 0OAI 8 .O i-rNEt >N F-- DEAD, PPh3, benzene F r C2F N 0( O C0213n 0 CO 2 Bn 0 CO 2 R 54 Pd(P~h3)a, 1,3-climethyl- 91 R 1 = AIL R 2 = Alloc H 2 , Pd(OH,) 2 -C x5RBi barbituric acid, GHC,IEt0Ac 92 R- R2 - H MeOH, THE Ex.57 R =H Core 05 Scheme 9 NHE~cNHBoc NHBoc 1-0,n Allac -12> 2N OH CO 2 AIIll=Y T3P, CH- 2 C4 2 0 N 81 0 N 0 Pr 2 NEt IF N ij N,-,COR 1 F N " -DEAD, PRn benzene FFo O 00280 0 00280 0 (5O 2 R 56 PdIPPh 3
)
4 , 1,3-dirnethyl- 93R = AIL R 2 = Alloc, H 2 , Pd(OHI 2 'C Ex.85 R -- Bin 10barbiterin acid, CH 0 1C~l 94 Et=O'= MeOH, THE Ex.86 R - H WO 2011/015241 PCT/EP2009/060168 403 Core 06 Scheme 10 NHBcc NHBoc NHBoc H-,,N Alloc [ NH NO 2 lR 322 T3Pc, GH 2 CI2 IN / OH C~l 2 o0 i-Pr 2 NBI 0 T N~F IF__N_____ _______ IN 0 CO 2 B3n 0 CO 2 13n 0 C0 2 R 56 Pd(PPh0) 4 , I ,5-dimethyl- 95 R' =Al R 2 = Alloc, H 2 , Pd(OH) 2 -O x14R-B barbituric aid, CHzClz,/EtOAc - 96 R 1 = R' H MeaCH Ex., OSR=H Core 02 andCore 07 Scheme 11 Bo oo Boo Io IN N N OH 1OAI 22~R NaCO,, 2 OJloc C0AI 2 Allc 0 C2R H 2 0, dioxane N I A N ADDP, Px3 CH1N F N<N..,IC 2 H O CO 2 Bn 0 CO 2 Bn 0 CO 2 B3n 54Pd(PPh 3 )4, 1 .3-dimethyl- 97 R' = All, R 2 = AlInc 99 barbituric acid, CH 2
CI
2 IEtOAc 98 R1 = R 2 -H p-TsOH H-Sar-OAII (46) T3P, i-Pr 2 NEt, AU Ot r2tI
CH
2 C1 2 Boo N N0 ,..)T3P, i-Pr2N~t, 0H 2 C1 2 I 2 0 0r~ N' 0 N F N N N F 0 COBn O CO 2 13n 0 C0 2 R Ex.2 H 2 . Pd(OFI) 2 -C Ex.115 R = Bn Pd(PPh 3
)
4 , 1,3-dirnethyl- 100 R1 All, R 2 Ad IOC MeOH Ex.116R=H barbiturio acid, CH 2
CI
2 /BtCAc 101 R 1 =R 2 = H 5 Core 08 Scheme 12 Boo Boc N. H C0 2 AIl 84 0 KN 'Alloc N. /-/N- T31P, i-Pr 2 NBI,0 _ 0 OH 2 0I 2 N. N F-( N_ CMBP, toluene F '- N.-.~ R IF -() N O CO 2 B3r 0 00 2 I0n 0 C0 2 R 56 Pd(PPh 2 j)4, I3-dimethyl- F -102 R' = All, R 2 = Abloc HII, Pd(OH) 2 -C - x.132 R n barbituric acid, CHCI 2 IBIOAc - 10R=R=I MoO] Ex.133 R = H WO 2011/015241 PCT/EP2009/060168 404 Core 0S Scheme 13 NHBcC NHBoc NHBoc I0AI 0T3P, CH C1 2 0 OH 00A1 36 'A0/ 0 R 2 T / 0 i-Pr 2 NEtI I N N,,-,,C0OR* IN F7(: -I'MBP. toluene F-a F-( 0 0 C0 2 B3n 0 CO 2 B3n 0 C0 2 R 54Pd(PPhi) 4 , i,53-dimethyl- 104 R' = All. R' = Alloc, H 2 , Pd(OH) 2 -C x12R-B barbituric acid, CHzCl,/Et0Ae 105 R' = R =H MeuCH Ex., 43 R =H Scheme 14 Core 10 TeocHN, RHIN, - H~oc Iq2- NH~bz OH A1102C NHCbz HON .&.I) 0 R02C NHCbz 16 Alloc DPDM 0 CMBP. toluene 0 0 63 1,3-dimnethylbarbituric acid, F - 106 R 1 = All, R 2 =Ailoc - x14R=To PdPh),C22MC 107 R' = R 2 =H TBFTFL Ex.65 R= H 5 Core 11 Scheme 15 NHTeoc
CO
2 AII L>TeacHNI RH NI OH NHCbz H0_,, N JN-R2 C7N 0 N.16 X1c-T3P, i-PI- 2 NEt. 0 CMBP, toluene N.NHCbz 65 0 0 1dFP3413-imty-08 R' = All, R 2 = AIIoc BFTH Ex.1 81 R = Teoc barbituriG acid, CH 2
CI
2 /Et0Ac 1:09 R' = R2 H Ex.,182 R= H WO 2011/015241 PCT/EP2009/060168 405 Core 12 (linear synthesis) Scheme 16 bHeo TeocHN' TecHN1 OH C0 2 AJI N Ij~~2AllocCi. dioxane, /iIJN -Alloc N -NHCbz 16 Allo
-
eqO~ a. Na2CO 3 , . N, 0C00R 0DEAD, PPh 3 , benzene r-NH~zNH 0 0 Pd(PPh1V,13-dimnethyl- 110 R 1 = All, R 2 =Alloc 112 barbituric acid, CH 2 CI2JEtOAo Il R= RI H p-TsOH H-Sar-OAI (46) HATU, HOAt; [-Pr N!Et RHN TeocHN, -~ 0 CNN-
CO
2 R' 0 N ~ FDPP, DMF 0 0 N, N NHCbz N NHCbz - N~ N o 0 H~ ioae Ex.1 96 R=-Teoc Pd(PPh 3
)
4 13-dimethyl- 113 R 1 n-All R 2 Alloc HIdoae Ex.197RB= H barbituric acid, CH 2
CI
2 /EtOAc F 114 RI = R 2 = H Core 12 (convergent synthesis) Scheme 17 PHBoc OH C 2 AI H,,1> BOCl-lN RHN, 0 RHNI 0 Q0AI "N -lo N N NH~b 81d- 2T3P, i-rN;,N I N EAD, PPha, benzene N N~z~N~z N 'Hb (to give 116.1) 1ib 'l! or ,. N~ N ~ N 69 CMdEP toluene (to give 116.Z 0 PO(PPh,),1,3-dimethyl- 116 B' All, R'- Alloc HOl- Ex.198 R = Boo HO- Ex.231 R = Boc 5 barbiturie acd, CF ChIE-.OAc 116 B = H dioxane EML97 RB-H dioxano Ex22 - WO 2011/015241 PCT/EP2009/060168 406 Core 13 Scheme 18 N HTeoo Te-ocHN Tec HN OH CONA HON N RN~2 Alloc.Cl, dioxane, >7'N.Aloc N NHCbz 20 Aoc- aq. Na 2
GO
3 , N, 0 C0RH 0DEAD, PPh 3 , benzene r-NH~zNH 59 0 Pd(PPh 3
)
4 , 1,3-dimethyl- 117 R I All. R 2 -Aloc 119 barbituric acid, CH- 2 Ck/EtOAC 118 R' R H p-TsOH H-Sar-OAll (46) HATU, HOAt, i-Pr 2 NEt RHN TeocHN ON' NIR C0 2 R' 0 N ~ FDPP. DMF 02 0 N, N NbzN rN cb o 0 HCI -dioxane Ex.21 5 R -Tec Pd(PPh 3
)
4 13-dimethyl- 120 RI n-All R 2 Alloc Ex.21 6 P H barbituric acid, CH 2
CI
2 /EtOAc F 121 RI = R2 H Core 14 Scheme 19 YHBoc OH C0 2 AII N _/N-N (JN CJ K."NI-Cloz 0 N N 81 COO FDPR DMF 0- , a DEAD, PPh3, benzene N ~ NH~bz N "Hbz N NHCbz 0 0 0 Pd(PPh),1,3-dimthyl- 122 RI = All, R 2 = Alloc H~- Ex.231 R = Boc HCI0. Ex.198 R = Boc barbituric acid. CI- 2
CI
2 IEtOAc - 123 R' = R~ 2- H dioxaeL..... Ex.232R =H dioxane[-E.9 5 WO 2011/015241 PCT/EP2009/060168 407 Core 15 andCore 16 Scheme 20 NH Boo HC-,< N NHCbz BocHN, NHCbz BocHN.\ 0 Hb OH5 Umnicore M2 85' Catalyst 0 DEAD. PPh 3 , benzene .. - 5 - CH 2
C
2 " 0 ~ 77 0 0 124 Ex.238
H
2 , Pd(OH) 2 -C, MeD H/THF BocHN, 0 (N
NH
2 0 ~ 0 Ex.239 Core 17 Scheme 21 NHBoc NHBoc NHBoc H,[:: HO_,[ N Alloc N'oVN HO CO 2 AIlyI ,N - N R 2 T3P, i-Pr 2 NEt I" - N 82 0 0,: 0N CO 2 Rr CH 2
CI
2 0 N0 C023 DED P~n 2 , benzene I N - N 88 0 CO 2 B3n 0 CO 2 R PdPh),13dmty-125 R'-= All, R 2 =Alloc H2P(H2CEx.248 R = Bn barbituric acid, CHv 2
C'
2 EtOAc, 12 R1R H MeOH/THF I Ex.249 R =H 5 Core 18 Scheme 22 NHBec 0 M-H R'HN OH COAIyi N ,N-Allec \/ C N-. C3.CHC 2 <NHCbz 81 0 0 R T, CH2C2, t 0 DEAD, PEE benzene N, K 7NHCE2 0 Pd(Ph,),1,-diretryl-127 RI = All, WRm Alc H - Ex.272 R' = Bec. R 2 = Cbz barbituric acid. CH 2
CI
2 ,/EtOAc L 128 R = R 2 =H diwsra, E.7RI=HCR2=le 'I()-c, IMeGH Ex.274 R 1 = Bc, R 2 = H WO 2011/015241 PCT/EP2009/060168 408 Core 19 Scheme 23 HH~ocNH~oc ,NH~ocQtij N N 0 NJ 81N 0T3P, f-rNI I I I CH 2
CI
2 N Ny .OAll N~ N-C0 2
R
1 - N; 0 co 2 Bn CMBP, toluene 0 Co 2 Bn 0 C0 2 R 75 1.3-dimethylbarbituric acid, 12 1=Al 2=AlcH 2 , Pd(0H)2-C, Ex27R=B Pd(PPh ), 0H- 2 0 2 /EtOAO 130 R 1 = 2=H MPOH I EX.298 R =H Care 20 Scheme 24 NJHTeoc NH~~oc *NH~cc AllocCi, dioxane,I - NHo / 6Alloc / eq /r Y Hb N NHCbz 1-N NHCbz. NaCO OH 0 'L AlDEAD, PPh 3 , benzene 0 72 C0 2 AI ~R2 C0 2 R 1 NAlc C2 TeocHN TeocHN Pd(PPh3)4, 1,3-dimethyl- 11R lR lo 3 barbituric acid.CH 2
CI
2 , Et0Ac 132 R' R2= H p-TsOH H-SarOAI (46), HATU HOAt, i-Pr 2 NEt H~o NH Boc N 3,iF 2 NEt, CH 2 I N NHClbz 0J -)JHCbz 0NR N N R C 2 C\ TeocHN lTeocHN Ex.311 PdPh),13dmty-134 R' = All, R 2 =Alloc baroi~ie cid,CH 2
C
2 , EtOAc -135 R I = R 2 = H 5 Core 21 Scheme 25 BOCHN BocHN NH~o ZEe SOAIy HO10_ N Alc 0 0 2 C0AMNT3P, i-Pr 0 NEt N N82 0 6010f 2 R CH 2
CI
2 2 \0N 80 0 COBn 0 COEn Pd(PPh31 4 A 13-dirnethyl- 136 R' = Al, R 2 = Allic npA Ex.312 X =S barbituric acid, CI- 2
CI
2 iEOAc F 137 RI = R2= H CH 2
CI
2 Ex.313 X = S02, WO 2011/015241 PCT/EP2009/060168 409 Structures of Examples Scheme 26 R2 2 2
R
2 N N N N O N O N O 0j~ 0 TA10 0 ~ TNT:1 F N N F F F F O N F 0 0 CORI' 0 CORI 0 CORI 0 CORI 0 CORO Core 01 Core 02 Core 03 Core 04 Core 05 Ex.1 Ex.2 Ex.3 - Ex.55 Ex.56 - Ex.84 Ex.85 - Ex.103 definition of R-groups definition of R-groups definition of R-groups definition of R-groups definition of R-groups cf. Table 20 cf. Table 20 cf. Table 21 of. Table 22 cf Table 23 R' R2 N N N ONN 0 N N O N O 0 N F O F 0 F O F o o C0R0 0 COR 0 COR 0 0 COR0, Core 06 Core 07 Core 08 Core 09 Ex.104 Ex.114 Ex. 115Ex. 131 Ex.132 - Ex.141 Ex.142 - Ex.163 definition of R-groups definition of R-groups definition of R-groups definition of R
-
grops cf. Table 24 cf. Table 25 cf. Table 26 of. Table 27 Structures of Examples Scheme 26, count. R2 R R R2 Ro R N R QN 0 N N N N O R N- O N-O N 0 R 5 0 0y o.f0N 0 0
N
N N N N N N 'R o 0 0 0 0 0 Core 10 Core 11 Core 12 Core 13 Core 14 Core 15 Ex.164 - Ex-180 EL181 - Ex.195 Ex.196 - Ex.214 Ex.215 - Ex.230 Ex.231 - Ex.237 Ex. 238 definition of R-groups definition of R-groups definition of R-groups definition of R-groups definition of R-groups definition of R-groups of. Table28 cf. Table 29 cf. Table 30 cf. Table 31 cf. Table 32 cf. Table 33 R O R O R2 N 22 N N N N O N NN N N R5 N N RN 0 0 COR 0 0 0 COR 0 CORE Core 16 Core 17 Core IS Core 19 Core 20 Core 21 (X = 3, 802) Ex.239 - Ex,247 Ex.248 - Ex.271 Ex.272 - Ex.296 Ex297 - Ex310 Ex.311 Ex.312 - EL.313 definition of R-groups definition of R-groups definition of R-groups definition of R-groups definition of R-groups definition of R-groups cf. Table 33 cf. Table 34 cf. Table 35 of. Table 36 cf. Table 37 cf. Table 37 5 WO 2011/015241 PCT/EP2009/060168 410 Core 03; Selected Final Products Scheme 27 H NHBoc NHR N NN N 0 F ON F O-H 0 CO 2 H 0 O H 0 0 N H0 N Ex.4 F N NF 0 N,0 H Ex.27 R = Boc Ex.11 0 N Ex.28 R = H NHR N--H O0 O 0NN O F N 0 F N 00 N NH Ex.49 Ex.30 R = Boc Ex.55 R = H Core 03; Selected Final Products Scheme 27, cont. H N / 0 ~ $ H N H 2 - HN N 1tN -H H2 N-H 0 N H N 0 FIF N 0N 0 H _ 0 -: H F N' H 0 N NH Ex.12 Ex.55 Ex.16 NH2 N-H N-H H 0 0 N F ' N 0 ' N 0F ' N 0 0 C0 2 Br 0 0 F -C ;!F O F( O C2Bn 0 O OR 0 N'H NH Ex.5 Ex.53 R = Bn Ex.9 5 Ex.54 R = H WO 2011/015241 PCT/EP2009/060168 411 Core 11 and Core 12; Scheme 28 Selected Examples
H
2 N, Co 0Q N 0 0 NH4Cbz 0 ~ NHCbz tNY NN 0 0 Ex.182 Ex.184 HN HCIHE 9HN- / 'K 0 0 ' 00 0HNN N XNHCbz N jNHP, 0 I 0 0\ Ex 197 Ex.200 R -Cbz 0 Ex.202 R =H Ex.213 5 Core 11; Scheme 29 10 0 Derivatization on Solid SupportN TeocHN HCI H 2 N HN 2N TBF, TF, N 0 DFPE polystyrene -then eq. NdI, CH 2 01 2 1-NB c) NHR 0 NHAIIoc -10(OCH 3
)
3 , DCE o. NHAIlec N, N, N, 0 0 0 Ex.181 R = Cbz 1. H 2 , Pd(0H) 2 -C, 139 140 MeOH 138 R = Aloc 2. A mOCi, dH 2
CI
2 , aq, Nei dO 3 1 . 2-Naphthylacetic acid HATU,' i-Pr 2 NEt. -0 0 N H 2 dI 2 , DME N 2. Pd(PPh 3
)
4 , Phi 3 0 3. 2-Naphthylacetic acid - 0 ~ / N PyBOP, i-Pr 2 NEt, (N 0 0 N N 0 H 2
I
2 , DME 0 H -20% TEA i CH 2
CI
2 0 N N H NN 0 NN Ex.186 0 141 WO 2011/015241 PCT/EP2009/060168 412 Biological methods 1. Preparation of the example compounds 5 Example compounds were weighed on a Microbalance (Mettler MX5) and dissolved in 100% DMSO to a final concentration of 2.5 mM for Ca2 assays. Example compounds were dissolved in DMSO/H 2 0 90:10 to a final concentration of 10 mM for plasma stability determination and 10 metabolic stability determination. 2. Ca assays: GPCR assays for motilin receptor, prostaglandin F (FP) receptor and 5-hydroxytryptamine 2B (5-HT2B) receptor 15 Assays were performed using a FLIPR Tetra (Molecular Devices); the data analysis and FLIPR Tetra Operating-Soft ware was ScreenWorks version 2 (Molecular Devices). 20 Dose dependent agonist and antagonist activities were determined. Percentage activation and percentage inhibition values were determined. Percentage activation was determined upon initial addition of the sample compounds followed by 10 minutes incubation at 25 0 C. 25 Following compound incubation, reference agonists were added at
EC
80 to determine percentage inhibition. Reference agonists were purchased from reputable commercial 30 vendors and prepared according to specifications specific to each ligand. All handling of ligands were done to ensure proper control throughout the experiments. Test compounds were serially diluted with DMSO. Once the appropriate concentrations were attained, the compounds were 35 diluted into assay buffer.
WO 2011/015241 PCT/EP2009/060168 413 GPCR assay buffer: Assay buffer was a supplemented HBSS (Hank's Balanced Salt Solution). HBSS was supplemented with 20 mM HEPES (4-(2 hydroxyethyl)-piperazin-1-ethansulfonic acid) and 2.5 mM 5 Probenecid (Sigma P8761). Assay plate seeding: GPCR assays were performed using Ca 2 optimized hematopoietic cell lines (rat) with cultures never exceeding 90% confluency. 10 Cells were harvested and seeded (from cultures at less than 90% confluency) at 50000 cells/well for a 96-well plate (12500 cells/well for 384). After seeding, the assay plates were incubated for forty-five (45) minutes at room temperature. After room temperature incubation, the assay plates were 15 incubated at 37'C 5% CO, for 24 hours prior to assaying. Calcium Dye Loading: All GPCR assays were performed using Fluo-8 Ca" dye. Ca 2 ' dye was prepared at 1 x dye concentration in GPCR assay 20 buffer. After 24 hours of incubation, cells were washed with GPCR assay buffer, then Ca2-dye (100 JL/well) was added. The plates were incubated for 90 minutes at 30'C 5% CO 2 prior to FLIPR assay. 25 Agonist Assay: Compound plates were prepared to add 50 [LL/well during the agonist assay mode. During the FLIPR assay, 50 !L/well from the compound plate was diluted 3-fold into the existing 100 jL/well from the dye loading step. Therefore all compounds were 30 prepared as 3x the final concentration desired in the assay. After completion of the first single addition assay run, assay plate was removed from the FLIPR Tetra and placed at 25'C for seven (7) minutes before antagonist assay. 35 WO 2011/015241 PCT/EP2009/060168 414 Antagonist Assay: Using the EC 80 values determined during the agonist assay, all pre-incubated sample compound and reference antagonist (if applicable) wells were stimulated with EC 80 of reference 5 agonist (motilin; prostaglandin F2a). After the addition of the reference agonist fluorescence was monitored for 180 sec using FLIPR Tetra. Data analysis: 10 From the FLIPR data, with negative control correction enabled, the maximum statistic for each well was exported and percentage activation relative to Emax control was calculated. 15 3. Plasma Stability Human plasma (3-5 donors, Blutspendedienst SRK, Basel) and CD-1 mouse plasma (mixed gender pool >50 animals, Innovative 20 Research, CA, USA) are both sodium citrate stabilized. The assay is performed in triplicates at 10 pM compound concentration and 37 0 C. Samples are taken at 0, 15, 60, and 240 minutes and stopped by precipitation with 2 volumes of acetonitrile. The supernatant is collected, evaporated and 25 reconstituted in a 5% acetonitrile solution to be analyzed by HPLC/MS/MS. The resulting peak area counts are expressed in percent of the 0 value and used to determine the endpoint stability in % and the half life T in minutes. In order to monitor assay integrity the degradation of propantheline is 30 assayed with every experimental set 4. Metabolic Stability 35 Microsomes from a human 50 donor mixed gender pool and 1:1 mixtures of microsomes from CD-1 mouse single-gender pools are WO 2011/015241 PCT/EP2009/060168 415 purchased from Celsis (Belgium). The enzymatic reaction is performed in a buffer containing an NADPH regeneration system and microsomes with the following end concentrations: 100 mM potassium phosphate buffer (all from Sigma), 1 mg/mL glucose-6 5 phosphate, 1 mg/mL -nicotinamide adenine dinucleotide phosphate (NADP), 0.65 mg/mL magnesium chloride, 0.8 units/mL of glucose-6-phosphate dehydrogenase (prediluted with 5 mM citrate buffer), 10 pM compound and 1 mg/ml microsomal protein. Compounds are incubated at 37 0 C in duplicates and samples are 10 taken after 0, 20 and 60 minutes. After acetonitrile precipitation (2 volumes) and HPLC/MS/MS analysis metabolic turnover is expressed in % of the initial 0 minutes value and half life Tba (min) is calculated. Verapamil for human and propranolol for mouse are used as reference and are assayed 15 with every experimental set. - F.P. Guengerich, Analysis and Characterization of Enzymes; in: Principles and Methods of Toxicology; A.W. Hayes (Ed.) Raven Press: New York, 1989, 777-813. 20 - R. Singh et al., In vitro metabolism of a potent HIV-protease inhibitor (141W94) using rat, monkey and human liver S9, Rapid Commun. Mass Spectrom. 1996, 10, 1019-1026. 5. Results 25 The results of the experiments described under l.-4. (above) are indicated in Table 38 and Table 39 herein below.
WO 2011/015241 PCT/EP2009/060168 416 0 4) P4 41 9 bi 44-) o U Hr tt E-1 ~. (N a LO 0C 4) 0U P4 ' WN P 4) o) rl ( $60 N 0 4H HJ CA 9 0 0 0 4 w o 9 t) t~ t H00 0 ( H N - 0 Ow 4-) J 4) to 4 C C)C r4 0 'r *H 44) C 0 4) 0 .p 4-) .0 r.0 9.. o U 0 C CO C M4 4 -10 m A ( (0 N co 0 N 0 4 0 -1 4-)C C o H 40 Lo H - *H) 44 o- H VU0 H 4-) 4-) 0' co CY) ~ ~ ~ -1 CA oD m 10 0 CD 0 H- H- H1 mY WO 0 H- Cl HZ~ X x xx E-4 '
_______________O
WO 2011/015241 PCT/EP2009/060168 417 cu - co m 0 Lo n I a OD - ( I- LO C m 00 0 G a H a) cm a~ c)m 0 H "-1 p H w a a-m ao c) o -n o o ' c) o a) o o N cm o o -H U) .- Q o 4 -H O~ 0 O N 0 CD 31 CD D 1 D 0 M LO 0 LC ro C)U co a a 1- a a Cm a0 aD co a cm co a Lo co cm -A -r -A 0 cmj cm cm cmj cm cm cm cm cm cm cm cm cm cm cm cm cm ~0 C!I ca H -) 4V) S N cm cm cm c cm m cm cm cm cm cm) cm cm cm cm cm0 c H) 0N 0) 0Y N f DH(O )~ o U) 0 rH H- H- (Y m -V q* r- a)~ 0) C7) a) H- H- r H Wxxxxxxxxxxxx -x niq w~ W~ Wi wi Ni W~n1n ~n WO 2011/015241 PCT/EP2009/060168 418 CC 0 0 H >ln a ) 0 0 Q0 0' N QN0 0 Q0 0 0 CD~~ ~ ~ Q0 0 ->C 0 0 -A Cl 0 C9 09 0 P4 ~ 0 0 o 0 0 0 0 0 00 0N (N ( (N N (N (N ( H 1 C C H HO

Claims (9)

1. Compounds of the general formula I incorporating the 5 building blocks A, B and C R1R O a x R 4 -N R 3 N R3 or B C b RR0 N R4Ni c2 c3 VV-( R 5 , 6 R7, 8 R 9 - 10 0 0-1 0-1 I I_________________ wherein the encircled moieties a in building block A, b in building block B and cl-C3 in building block C are derived from basic skeletons, appropriately and independently 10 substituted as defined below, the basic skeletons of a and b corresponding to the ring systems depicted in Table 1 and Table 2, below; )N N al a2 a3 a4 NZ"N N. N N- N a5 a6 a7 a8 yN a9a10N Y a12 a9 alO all a12 WO 2011/015241 PCT/EP2009/060168 420 N N N a13 a14 a15 a16 N N N a17 a18 a19 a20 N N N N N N CN N N c a21 a22 a23 a24 a25 Table 2: Ring Systems bl-bl of Building Blocks B ,, N NO,, b1 b2 b3 b4 N IR1 N I,N /b b5 b6 b7 b8 N b9 blO bl 5 WO 2011/015241 PCT/EP2009/060168 421 depending on the substitution pattern of skeletons b alternative binding modes being feasible for skeletons b3 and b4 such incorporation via the excocyclic nitrogen atom being represented by the following two 5 structures: , R3 ,, R3 N'R11 N' R" NN 'R4 R4 the encircled parts of the bridge subunits c1-c3 representing optionally substituted groups, defintions of 10 c1-c3 being depicted in Table 3, below, each reading from the N-terminus to the C-terminus of the linker C, said linker C being, in the simplest case, constituted by one subunit c1, i.e. cl-1 to c1-6,and for the embodiments consisting of two or three subunits all possible 15 combinations of the subunits c1-c3 and the connectivities U, V and W being possible; Table 3: Scope of Subunits of c1-c3 of the Linker Group C 00 0 N 0 0 OR 20 0-1 0-1 j%-- 20 0 V,W= - NR 4 R R 12 R 13 R 1 2 R 13 0 0 5 R5 R14 R14 R5 cRii-iCi 6 R 6 R 15 R 1 5 R 6 1-2 1-2 c1-1 c1-2 c1-3 WO 2011/015241 PCT/EP2009/060168 422 R 14 R 5 R 14 R R 4 4 R5 - 1 15 R 6 R 15 R 6 R 15 j R 6
3-5 3-5 cl-4 cl-5 cl-6 7 R 7 R16]R 16 Rp 7 A 8 R17 R17 8 1-2 1-2 ' c2-1 c2-2 c2-3 C2 R 16 R 7 R 16 R 7 R16] 16 p 7 6 -, 6-- --6 - 5--- 17 R 8 R 17 R 8 R 1 7 LR 1 7 R 8 3-5 3-5 c2-4 c2-5 c2-6 R9 R 9 R 16 R 16 R 9 - - --C-- --- --- C-C- C3 110 17 17 10 c3-1 c3-2 c3-3 the substituents directly attached to building block A,B and C, i.e. R'-R", being defined as follows: 5 R : H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; -(CR 8 R 9) qOR 20 ; - (CR R 9) qSR 20 ; - (CR R 9) qNR 4 R''; 10 - (CRR 9 ) qOCONR 4 R"; - (CRR 9 ) qOCOOR 21 ; - (CR' 8 R' 9 ) qNR 4 COOR; 21 - (CR "R 9) qNR 4COR2; - (CR 8 R1 9 ) qNR4CONR4R"; - (CR' 8 R' 9 ) qNR4S0 2 R 23 ; - (CRR 9 ) qNR 4 SO 2 NR 4 R"; - (CRR1 9 ) qCOOR 21 ; - (CR' 8 R' 9 ) qCONR 4 R"; - (CR "R 9) qSO 2 NR 4 R"; - (CR' 8 R' 9 ) qPO (OR 21 ) 2; - (CR' 8 R' 9 ) qOPO (OR ) 2; - (CR R 9 ) qCOR; 22 - (CR' 8 R1 9 ) qSO 2 R 23 ; - (CR' 8 R1 9 ) qOSO 3 R; 2 1 15 -(CR 1R 9) qR 24 ; -(CR 1R 9) qR2; or - (CR 8 R1 9 ) qR2; WO 2011/015241 PCT/EP2009/060168 423 R 2:H; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 8 R 9 ) qOR 20 ; 5 - (CR R 9) qSR 20 ; - (CR"R1 9 ) qNR 4 R"; - (CR"R' 9 ) qOCONR 4 R"; - (CR"R'9) qOCOOR 2 1 ; - (CR'"R' 9 ) qNR 4 COOR 2 1 ; - (CR'"R' 9 ) qNR 4 COR 2 2 ; - (CR"R 9) qNR 4CONR4 R"; - (CR"R 9) qNR 4 SO 2 R 2 3 ; - (CR'"R' 9 ) qNR 4 SO 2 NR 4 R"; - (CR"R 9) qCOOR 2 1 ; - (CR'"R1 9 ) qCONR 4 R"; - (CR"R19) qSO 2 NR 4 R"; - (CR"R 9) qPO (OR 2 1 ) 2; - (CR R 19) qCOR 2 ; - (CR"R19) qSO 2 R 2 3 ; 10 - (CR R 9) qR24; -(CR R )qR 2; or - (CRR 9 ) qR; 2 6 R 3 : H; CF 3 ; alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 15 R 4 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or a suitable N-protecting group; 20 R , R 7 and R 9 are independently defined as: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR R 9) OR 2 0 ; - (CR R 9) SR 2 0 ; - (CR"R 9) sNR 4 R"; - (CR"R 9) SOCONR4 R1; - (CR"R 9) sOCOOR 2 1 ; - (CR"R 9) sNR 4COOR 2; 25 - (CR"R 9) sNR 4COR - (CR1 8 R' 9 ) sNR 4 CONR 4 R"; - (CR'"R' 9 ) sNR 4 SO 2 R 2 3 ; - (CR'R') sNR4SO 2 NR4R"; - (CR"R 9) qCOOR 2 1 ; - (CR'"R1 9 ) qCONR 4 R"; - (CR'"R' 9 ) qSO 2 NR 4 R1; - (CR'"R' 9 ) qPO (OR 2 1 ) 2; - (CR R 9) qCOR 2 ; - (CR'"R1 9 ) qSO 2 R 2 3 ; - (CR1 8 R1 9 ) qR 24 ; - (CR1 8 R1 9 ) qR 2 5 ; or 30 - (CR R )qR 2; R , R 8 and R 10 are independently defined as: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; or heteroarylalkyl; 35 WO 2011/015241 PCT/EP2009/060168 424 R": H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable protecting group; -(CR 8 R19) rOR 20 ; - (CR 8 R 9) rSR 2 0 ; - (CRR'9) rNR 4 R 2 1; 5 - (CR R'9) rOCONR4R 7 ; - (CR'8R19) rOCOOR 2 1 ; - (CR R 9) rNR4COOR'; - (CR R1 9 ) rNR 4 CONR 4 R 2 7; - (CR R 9 ) _NR 4 SO 2 R 2 ; - (CR' 8 R' 9 ) rNR 4 SO 2 NR 4 R 2 7; - (CR R1 9 ) qCOOR 2 1 ; - (CR' 8 R' 9 ) qCONR 4 R 2 7; - (CR R 9 ) qCOR 2 2 ; - (CR R1 9 ) qSO 2 R 2 3 ; - (CR 8 R 9 ) qSO 2 NR 4 R 2 7; - (CR 8 R 9 ) qR 24 ; - (CR 8 R' 9 ) R 25 ; or - (CR' 8 R1 9 ) qR; 2 6 10 R and R" are independently defined as H; or alkyl; R 4 and R' 6 are independently defined as: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; 15 heteroaryl; arylalkyl; heteroarylalkyl; - (CR R 9) sOR 2 0 ; - (CR"R 9) sNR4R"; - (CR'"R' 9 ) sNR 4 COOR 2 1 ; - (CR"R 9) sNR 4COR - (CR' 8 R' 9 ) sNR 4 CONR 4 R"; - (CR'"R' 9 ) sNR 4 SO 2 R 2 3 ; - (CR"R 9) sNR4SO 2 NR 4 R"; - (CR"R19) qCOOR 21 ; - (CR'"R' 9 ) qCONR 4 R"; - (CR"R 9) qSO 2 NR4R"; or - (CR"R") qCOR 2 2 ; 20 R 15 and R' 7 are independently defined as: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; or heteroarylalkyl; 25 substituents introduced in the sub-definitions of the radicals R -R1 being defined as follows: R : H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; 30 heteroarylalkyl; - (CR 29 R 30 ) sOR 3 ; - (CR 29R ) sSR 3 1 ; - (CR 29R ) sNR 28R ; - (CR 29 R 30 ) sOCONR 2R ; - (CR 29R ) sOCOOR 21 ; - (CR 29 R 30 ) sNR 28 COOR 21 ; - (CR 29R ) sNR 2COR 1; - (CR 29 R 30 ) sNR 2 CONR R ; - (CR 29 R 30 ) sNR 2 8 SO 2 R; 2 3 - (CR 29R ) sNR SO 2 NR R ; - (CR 2 9 R 3 0 ) qCOOR 21 ; - (CR 2 9 R 30 ) qCONR 2 "R 31 ; 35 - (CR R ) qSO 2 NR R 3 1 ; - (CR 29 R 30 ) qPO (OR 2 1 ) 2; - (CR 2 9 R 3 0 ) qCOR 3 1 ; WO 2011/015241 PCT/EP2009/060168 425 - (CR 29R ) qS0 2 R 23 ; - (CR 29 R 3 0 ) qR 24 ; - (CR 29 R 30 ) qR 25 ; or - (CR 29 R 3 0 ) qR 26 ; R 9 : H; CF 3 ; alkyl; alkenyl; cycloalkyl; 5 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; R2 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 10 - (CR 29R3 ) rOR 31 - (CR29 ) rSR 31 . - 29 30) 28 31 29R 30 28R 31 -(R29R 30 N 2 8C 21 (CR R )rNR R ; - (CR R )rOCONR R ; -(CR R )rNR COLOR - (CR 29R3 ) rNR 2COR 1; - (CR 29 R 3 0 ) rNR 28 CONR 2R ; - (CR 29 R 3 0 ) rNR 28 S0 2 R; 23 -(CR 29R3 )rNR 2SO 2 NR 28R; - (CR 29R ) qCOOR 21 ; - (CR 29 R 3 0 ) qCONR 2 8 R 31 ; - (CR R ) qSO 2 NR 2R ; 15 - (CR 29R ) qCOR 31 ; - (CR 29 R 3 0 ) qSO 2 R 23 ; - (CR 29 R 3 0 ) qR 24 ; - (CR 29 R 3 0 ) qR 25 ; or - ( CR29R 30 26; R 2 alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or a suitable 20 0-protecting group. R2: alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 29 30) 3 29 30) 3 29 30 ) 28 31. -(CR R ) OR; -(CRR ) SR; -(CRR ) SNR R 25 - (CR 29R ) SOCONR 2R 31 ; - (CR 29R ) sNR 2COOR ; - (CR 29 R 3 0 ) sNR 28 COR 31 ; -(CR R ) SNR CONR R ; -(CR R0 )S NR S0 2 R 3 ; -(CR 29R )S NR SO 2 NR R3; - (CR 29R ) COOR 2 1 ; - (CR 29 R 3 0 ) sCONR 2 "R 31 ; - (CR 29R ) sS0 2 NR R3; - (CR 29R ) 7 COR 31 ; - (CR 29 R 3 0 ) sS0 2 R 23 ; - (CR 29 R 3 0 ) tR 24 ; - (CR 29 R 3 0 ) tR 25 ; or 30 -(CR 29R ) tR2; R2: H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or - (CR 32 R 33 ) tR 24 ; 35 WO 2011/015241 PCT/EP2009/060168 426 R 24: aryl, preferably an optionally substituted phenyl group of type C 6 H2R 34 R 35 R 31 ; or a heteroaryl group, preferably one of the groups of formulae H1-H34 as shown in Table 4, below; 5 Table 4: Groups of Formulae H1-H34 R 3 4 NR3 R 34 N R 34 Y y Y Y H1 H2 H3 H4 R7) 3 6 -- ~ -- 'p R~ 3 H5 H6 H7 H8 N N H9 H10 H1 H12 R R4 3 4 N R 3 4 NNR 3 4 N R 3 N NN N N H13 H14 H15 H16 ( N N R3 'z 6N R 34 N R 3 R 36 R R34 Umbruch H17 H18 H19 H20 R 34 R 34 H 2 \H H23 H24 y R 4 Y Y y> R3 H21 H22 H23 H24 WO 2011/015241 PCT/EP2009/060168 427 _ _R 34 R34 R 34 N N. .- N.. N N.. -N H25 H26 H27 H28 N3 RN R 34 N0 34 N 34 >R R R 3 N ~ N KN H29 H30 H31 H32 -R34 RNIz 34 N( R 36 H33 H34 R : One of the groups of formulae H35-H41 as shown in Table 5, below; 5 Table 5: Radicals of formulae H35-H41 R 38 R 38 R 38 R 38 I N N Z 37 x37' 'R37 37 H35 H36 H37 H38 R 3 4 R 3 4 R 3 4 R 35 35 3 N R 3 N ,N R 35 ' 37 ' R37 R7 H39 H40 H41 R : One of the groups of formulae H42-H50 as shown in Table 6, below; 10 WO 2011/015241 PCT/EP2009/060168 428 Table 6: Groups of Formulae H43-H50 R38 R 38 R 38 R38 NR37 37 37 N37 H42 H43 H44 H45 R 34 _ C 38 R/3 R 3 4 SNR38N R 35 -- R 35 37 37 x37 R 38 ,3 H46 H47 H48 H49 R 38 R 34 N R 35 R37 H50 R : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; 5 aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable protecting group; or -(CR 29R )qR24; R : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; 10 aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable N protecting group; - (CR3 R ) sOR 2 ; - (CR R ) NR 43R 42; - (CR 32 R 33 ) SNR 4 2 CONR 43R42 32 33) 42 2132 3) R 2 2;2 331 - (CR R ) NR COR'; - (CR 3 R 3 ) NR 4 2 SO 2 NR 2 ; - (CR 3 R 3 ) qCOOR 2 ; - (CR3 R ) qCOR 2 3 ; - (CR 32 R 33 ) qSO 2 R 21 ; 15 R 29: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 32 R 33 ) sOR 3 ; WO 2011/015241 PCT/EP2009/060168 429 32 33 32 33 2 31 28 3 - (CR R ) sSR 3 ; - (CR R ) sNR 28R ; - (CR 32 R 3 3 ) SOCONR 2R3; - (CR3 R ) sOCOOR 2 1 ; - (CR 3 2 R 3 3 ) sNR 28 COOR 2 1 ; - (CR R ) sNR 2COR 1; - (CR 3 2 R 3 3 ) SNR 28 CONR 2R ; - (CR 3 2 R 3 3 ) sNR 28 SO 2 R 2 3 ; 5 - (CR R ) sNR 2SO 2 NR 28R ; - (CR 3 2 R 3 3 ) qCOOR 2 1 ; - (CR 3 2 R 3 3 ) qCONR 28 R 3 1 ; - (CR3 R ) qSO 2 NR R 3 1 ; - (CR 3 2 3 3 ) qPO (OR 2 1 ) 2; - (CR 3 2 R 3 3 ) qCOR; 3 1 - (CR R ) qSO 2 R 23 ; - (CR R 3qR 31 ; R: 30 H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; 10 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; R 31 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or one of the 15 groups of formulae H51-H55 as shown in Table 7, below; Table 7: Groups of Formulae H51-H55 R39 R 39 OR 21 R 39 | 4 1 41 ---- C--R41- -- C---C---C- R4 R40 40q 4o R 40 q 0-20 q - s - u H51 H52 R 39 NR 28 R 43 R 39 R39 R 12 R 39 I (41 --- C-- C- -C- R 4 --- C- -C---C- R R40 R40 R40 R40 R13 R40 q .s -q -q - - -q u u H53 H54 R 39 R 39 1 11 -- -C--Q--C- R4 -40 R40 S5S H55 WO 2011/015241 PCT/EP2009/060168 430 R and R 33 are independently defined as H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 5 R 34 and R 35 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 29 R 3 0 ) qOR 3 ; -(CR 29R ) qSR 3 1 ; - (CR 29R ) qNR 28R ; -(CR 29 R 3 0 )qOCONR 2R ; 10 - (CR 29R ) qNR 2COOR 2 1 ; - (CR 29R ) qNR 28 COR 3 1 ; - (CR 2 9 R 30 ) qNR 2CONR 28R; - (CR"R ) qNR2SO 2 R"; - (CR"R 30 ) qNR 2 8 SO 2 NR"R' ; -(CR 29R )q COOR 2 1 ; - (CR R ) qCONR 2R 1; - (CR 29 R3 ) qSO 2 NR 2R ; - (CR 29 R 30 ) qCOR 3 1 ; - (CR R ) qSO 2 R 23 ; or - (CR 29 R 30 ) qR; 31 15 R: 3 6 H; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; 2 3 heteroarylalkyl; or -NR 8 R 3 ; 20 R 3 7: H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; a suitable N-protecting group; 29 30) 3 29 30) 3 29 30 28 31 - (CRR ) rOR 3 ; -(CRR ) rSR 3 ; -(CRR ) rNR R ; (CR 29R3 )rOCONR 2R'; 25 - (CR 29R3 ) rNR 2COOR 2 1 ; - (CR 29R ) rNR 28 COR, 3 1 - (CR 29 R 30 ) rNR 28CONR 28R ; -(CR R3 )rNR SO 2 R ; - (CR2R30 ) rNR SO 2 NR R 31 ; -(CR2R30 ) qCOOR2; - (CR R ) qCONR 2R 1; - (CR 29 R3 ) rSO 2 NR 2R ; - (CR 29 R 30 ) qCOR; 3 1 - (CR R ) qSO 2 R 2 3 ; or - (CR 29 R 30 ) qR 31 ; 30 R 3: H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; -(CR 29 R 30 ) qOR 31 -(CR 29R ) qSR 3 1 ; - (CR 29R ) qNR 28R ; - (CR R ) qNR 2COOR 2 1 ; - (CR 29R ) qNR 28 COR 3 1 ; - (CR 2 9 R 30 ) qNR 2CONR 28R; - (CR R ) qCOOR 21 ; - (CR 2 9 R 30 ) qCONR 28 R 31 ; - (CR 29R ) qCOR 31 ; or 35 -(CR 29R3 )qR 31 ; WO 2011/015241 PCT/EP2009/060168 431 R 39 : H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 32 R 33 ) uOR 2 ; - (CR R ) NR 2R 43; - (CR 32 R 33 ) tCOOR 2 1 ; or - (CR R ) tCONR 28R43 5 R 40 : H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; - (CR 3 2 R 3 3 ) uOR 2 ; 32 33) 28 43; 32 33) C~ 2 (R3 3 C N 28 R43 - (CR R ) uNR BR; - (CR 3 R 3 ) COLO R ; or - (CR R ) LCONR R 10 R 41 : H; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; 21 28 43 28 2 2 2 heteroarylalkyl; -OR 2 ; -NR "R ; -NR "COR 3 ; -NR 28 COOR ; -NR 2SO2R23; -NR 2 CONR2"R43; -COORs2; -CONR 2R 43; -C(=NR 43 )NR 2N43; 15 -NR 28 C (=NR 43 )NR 28 N 43 ; or one of the groups of formulae H56-H11O as shown in Table 8, below; Table 8: Groups of Formulae H56-H11O R 44 R 44 R 44 R 44 _ R 46 R 45 R 45 R 45 H56 H57 H58 H59 N R 44 N R 44 -- N 44 R4 N N N-_N H60 H61 H62 H63 R 44 R 44 R 44 R 44 - N --- /-- --- \ N N-N N-N N-N H64 H65 H66 H67 WO 2011/015241 PCT/EP2009/060168 432 R 44 R 44 R 44 R 44 - \ - Q------N N Q H68 H69 H70 H71 R 44 N R 44 R 44 R 44 - -N - .. I- N Q Q N' H72 H73 H74 H75 - - -N -N -N Q 44 N N N H76 H77 H78 H79 R 45 R 45 R44 R44 T T T 1-N T --- N \ --- N N -- -- \ / R 44 R 44 H80 H81 H82 H83 N45 R-T 45 RR45 R TT R45 R5 g- T 44 4 T44 R -- R T N NN R44 H88 H89 H90 H91 WO 2011/015241 PCT/EP2009/060168 433 R 45 R44 R44 T R44 R4 R R R k TyT- T -- Q-c NQ H92 H93 H94 H95 T T R T R 44 R 48 T R49 ---- N N N yN R 47 --- N N, R 3 6 R47N q H96 H97 H98 H99 49 49 R QR R298 Q 0-6 R-5 - - 0-2 R R9 0-2 R H104 H105 H106 H106 R49 -R49[__-R49 H108 H109 H11 42l R42 H; alkyl; alkenyl; cycloalkyl; cycloheteroalkyl; aryl; heteroaryl; R 33 2R 33 2 N 43 5 - (CR 23R 3) OR 2 1 ; (CR 23R 3) NR 28R 43; -(CR 2 3 R 3 3 ) qCOOR 2 1 ; WO 2011/015241 PCT/EP2009/060168 434 or - (CR 2 3 R 3 3 ) qCONR 2 'R 43 ; R 43 : H; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; or a suitable 5 N-protecting group; R 44 , R 45 and R 46 are independently defined as H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; 10 heteroarylalkyl; -OR 23 ; -NR R 43; -NR COR 23 ; -NR"SO 2 R"; -NR"CONRR 41; -COR"; -SO 2 R2; R 47 : H; CF 3 ; alkyl; alkenyl; alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; 15 heteroarylalkyl; -COOR ; or -CONR R43; R 48: H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; cycloheteroalkyl; aryl; heteroaryl; - (CR R ) tOR 21 ; - (CR R ) NR R 43; - (CR 2 3 R 3 3 ) tCOOR 2 1 ; 20 -(CR2R3) CONR R4 3 ; R 49 and R 50 are independently defined as H; F; CF 3 ; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; 25 -(CR3 R) OR 21 ; - (CRR) qNR R 43; -(CR 32 R 33 ) qCOOR 21 ; or -(CR3 R ) qCONR R4 3 ; taken together the following pairs of said substituents can define cyclic structural elements: 30 (R 4 and R") ; (R 4 and R 27 ) ; (R 5 and R 6 ) ; (R 5 and R 7 ) ; (R 5 and R 9 ) ; (R 5 and R 4 ) ; (R 5 and R 6 ) ; (R 7 and R") ; (R 7 and R 9 ) ; (R 7 and R1 6 ) ; (R 9 and R1 0 ) ; (R 4 and R1 5 ) ; (R1 6 and R1 7 ) ; (R"' and R 9) ; (R 2 7 and R 2 8 ) ; (R 2 " and R 3 1 ) ; (R 2 " and R 43 ) ; (R 29 and R 3 0 ) (R 3 2 and R 33 ) ; (R 34 and R 3 5 ) ; (R 3 7 and R 3 ) ; (R 39 and R 40 ) ; (R 39 35 and R 4 1 ) ; (R 3 9 and R 4 9 ) ; (R 42 and R 43 ) ; (R 4 4 and R 45 ) ; or (R 4 4 and WO 2011/015241 PCT/EP2009/060168 435 R 4 6) can form optionally substituted cycloalkyl or heterocycloalkyl moieties; in addition, the structural elements -NR 4 R"; -NR"R"; -NR8 R3 5 or -NR 28R 4 can form one of the groups of formulae H111-H118 as shown in Table 9, below; Table 9: Heterocyclic Groups Defined by Linking the Residues of the Disubstituted Amino Groups -NR 4 R"; -NR 2 7R 28 ; -NR 28 R 3 1 or 28 43 10 -NR R R 44 R R39 R 9 R49 T T - -Ns R 4N R49 -N Q R39 R 50 tR H111 H112 H113 H114 R 4 0T-\R44 R 49 H R4 R 50 TT -NR4 H H -- N -N> QR9- -Nq H R 49 t i 9\_ R5o R 5o H115 H116 H117 H118 variable heteroatoms and connector groups in the aforementioned structures being as follows: 15 Z : 0; S; S (=0) ; S(=0) 2 ; or NR28; Y: 0; S; or NR3; X: 0; S; S (=0) ; or S (=O) 2 ; Q: 0; S; or NR28; U, V and W: as defined in Table 3, above; 20 T: CR46 or N; in case T occurs several times in the same ring structure each T being defined independently of the other; and WO 2011/015241 PCT/EP2009/060168 436 the indices being defined as follows: q=0-4; r=2-4; s=1-4; t=0-2; and u=1-2; all possible stereoismers and pharmaceutical acceptable salts thereof. 5 2. Compounds according to claim 1 wherein A is a bivalent radical selected from radicals Al - A626 as depicted in Table 10, below; 10 Table 10: Radicals Al(al)-A626(a25) R R R1 R 1 X XI X X, 00 Al(al) A2(al) A3(al) A4(al) 0 ax 0, o,,a 0 Nx RR OX 0 0 O X A5(al) A6(al) A7(al) A8(al) o R 1 0 R 34 R 1 X ' R 1 X ' A9(al) A10(al) All(al) A12(al) 3R4 R 34 R R R 34 R1 X~' R3 X' (0 0 A13(al) A14(al) A15(al) A16(al) WO 2011/015241 PCT/EP2009/060168 437 lR 34 R lI R 34 34 R R 4 X, ,X R4 X, 00 0~ 0 A17 (al) A18 (al) A19 (al) A20 (al) R 34 iR 34 3)1 R4 X, ~ 0 x p 5 1 A21 (al) A22 (al) A23 (al) A24 (al) R 4 0 0 R 34 0 R3 RiN RiN x R X R 51 R 34 A25 (al) A26 (al) A27 (al) A28 (al) R4R 35 R 34 R 35 R1 3R3 R 1 X, R 1 0 ,X R ~X" X" 0 0 0 A29 (al) A30 (al) A31 (al) A32 (al) R 34'RX" R 34 RX 34 X 4 X 00 A33 (al) A34 (al) A35 (al) A36 (al) R 34 R 5 R3 lR 35 R R 34 R35R X R 34 X, R3 "X 00 0 WO 2011/015241 PCT/EP2009/060168 438 A37 (al) A38 (al) A39 (al) A40 (al) R 34 R R 35 R3 R 35 R 3 R 35 :3D 4 0' N 0: x 0: N 0 I R 51 A41 (al) A42 (al) A43 (al) A44 (al) Or 34 :[, 35 R 34 R 35 0 435 03 R R 3 A45 (al) A46 (al) A47 (al) A48 (al) 0 R 3 4 0 R 3 4 0 0 R 3 4 -~ 34 -~ R 35 RN X R35 x R35 x N x R 35 lRlR A49 (al) A50 (al) A51 (al) A52 (al) Nl X R 3 4 X" R 34N X, R34N x A53 (al) A54 (al) A55 (al) A56 (al) RR 0 R35 34 R 35 520 R34 R3 0 R 34 N -- iR x 51 R 52 0 A57 (al) A58 (al) A59 (al) A60 (a2) WO 2011/015241 PCT/EP2009/060168 439 IN RN R 1 IN R1~ x R X, N X, 00 0~ 0 A61 (a2) A62 (a2) A63 (a2) A64 (a2) N IN X, IN XX, XN X A659(a2) A660(a2) A7 (a2) A682(a2) R 1 N RN NNNR 0 0 0 0 x N X X A73 (a2) A74 (a2) A75 (a2) A7 6(a2) Ri R R1 N R 1 IN 0 NN X10 1 IN I xx A77 (a2) A78 (a2) A7 9(a2) A80 (a2) IN IN IN 0 00 0 A81 (a2) A82 (a2) A83 (a2) A84 (a2) WO 2011/015241 PCT/EP2009/060168 440 o 0 0 0 N XN - - N R1 X R1,], X NN x x A85 (a2) A86 (a2) A87 (a2) A88 (a2) o R 36 R 34 R 36 N X N'I N~ x R R1 X' R1 X" l 0~ 0 0 A89 (a2) A90 (a2) A91 (a2) A92 (a2) N R3 R34R 36 R 34 N 36 R 3 N RN R1 X, R 1 ~ X R N- X 000 A93 (a2) A94 (a2) A95 (a2) A96 (a2) l R 36 R 1 N R 1 N R 36 R N N NN N X, R 3 4 X, X, 6 X, 00 0 0 A97 (a2) A98 (a2) A99 (a2) A100 (a2) R 36 R lR R1 -, N R 36 R3 - ~N- N 00 0 0 A101 (a2) A102 (a2) A103 (a2) A104 (a2) N R R 34 R R 34 R R 36 R " R 36 X" "x, 0 A105 (a2) A106 (a2) A107 (a2) A108 (a2) WO 2011/015241 PCT/EP2009/060168 441 R 34 R R 36 N R -R36 X, R X, 0 0 0 0~ A109 (a2) A110O(a2) AM11(a2) A112 (a2) R 36 N R 1 R 1 N R 36 0 R 34 R 36 0X NNX YI I I 0 1 1 A113 (a 2) A114 (a2) A115 (a 2) A116 (a2) R 36 R lR 0:R 34 R 3 R 34 X 0 N' X N' X A117 (a2) A118 (a2) A119 (a2) A120 (a2) Rl ~~R 36 R 6N R 4 R R 3 6 RR36 N R 1 34 R3 I I RR 3 N o, N, 00 0 N ( 0 I A125 (a2) A126 (a2) A127 (a2) A128 (a2) N R 36 R 3 R~ 36 N R 36 00) 0X A129 (a2) A130 (a2) A131 (a 2) A132 (a2) WO 2011/015241 PCT/EP2009/060168 442 o 0 R 36 0 0 R 36 N- N X R Rl R 1 N X R 36 R 34 A133 (a2) A134 (a2) A135 (a2) A136 (a2) o 0 R 3 4 0 0 R- 34 R 36 -- N R 1 N X N~ x NR x Il Il I A137 (a2) A138 (a2) A139 (a2) A140 (a2) o o 0 R 3 6 N N R 36 N- X - S X R36 x x Il l l 0 A141 (a2) A142 (a2) A143 (a2) A144 (a3) N R 1 N. R 1 N. R N N A145 (a3) A146 (a3) A147 (a3) A148 (a3) N ii lR N NN R 1 NN R R 5 1 A149 (a3) A150 (a3) A151 (a3) A152 (a3) N. 0 R 1 N R 34 I N X N NN A153 (a3) A154 (a3) A155 (a3) A156 (a3) WO 2011/015241 PCT/EP2009/060168 443 N R' R 34 N, R 1 N, R N'~~ 'N' R 34 R 34 X, R-X 4 X" N X, o0 - 0 0 A157 (a3) A158 (a3) A159 (a3) A160 (a3) R 34 0 R 1 3 0 R 34 .N R 34 N Nl XNNN 0 R 5 N A1615(a 3) A1626(a43) A1637(a43) A1648(a3) 0, 511 R X, X, R 0 0 0 I" 0 r IX N1 X N X 0 0 N~ - 1 N X 0,,X5 R 1 N"X A173 (a4) A174 (a4) A175 (a4) A176 (a4) o R 1 N R 36 R 36 N R 1 R 36 N- N IiN N x 0? X l x" 0l 0 0 A177 (a4) A178 (a4) A179 (a4) A180 (a4) WO 2011/015241 PCT/EP2009/060168 444 Rl ~R 36 R 3N NNX 0 R R 3 N X :N X N X R I I I A181 (a4) A182 (a4) A183 (a4) A184 (a4) R 36 R 36 0 R 3 4 0 N N - - N - N R 3 6 0~ N 0: NR N< I I N X A185 (a4) A186 (a4) A187 (a4) A188 (a4) R NN R 1 R N NR 1 NN xr N X" 0 N x O,4 N X 0 ,'- 0" I A189 (a5) A190 (a5) Al 91(a 5) A192 (a5) o 0 R 34 R - N, -- N R 1 N 3 N R 1 CN X N ~X N X N 0 0, A193 (a5) A194 (a5) A195 (a5) A196 (a5) R 1 N R 34 R 34 N R 1 3 N X 3 R3 A197 (a5) A198 (a5) A199 (a5) A200 (a5) R 1 N Al R 1 N N R "N N NN ' N N X" N-r -" N X N IX 0", A201 (a6) A202 (a 6) A203 (a 6) A204 (a6) WO 2011/015241 PCT/EP2009/060168 445 o R' 0 Y\R ---- Nyi RiK x ' N X N NX A205 (a 6) A206 (a6) A207 (a7) A208 (a7) A209 (a7) A210 (a7) A211 (a 7) A212 (a 7) 0 y y A213 (a7) A214 (a7) A215 (a7) A216 (a7) 'I 5 RiK X R 34 " x 00 A217 (a7) A218 (a7) A219 (a7) A220 (a7) R 1 R 34 R 34 R 1 4R A221 (a7) A222 (a7) A223 (a7) A224 (a7) R 1 R 34 R 34 R 1 R 34 R 34 Y Y 0 /\0 /0 0 y x 'I XX A225 (a7) A226 (a7) A227 (a7) A228 (a7) WO 2011/015241 PCT/EP2009/060168 446 - NZX' 0 A229 (a8) A230 (a8) A231 (a8) A232 (a 8) Rl Ri ~Y-NN-R O 0j\ N A233 (a8) A234 (a8) A235 (a 9) A236 (a9) y lN-Y 0 Y-NI 0 - I 1R 1R A23 (a9 A23 (a)A3xa)A4 aO Y X, y " y x, 0l 0 A241 (alO) A242 (alO) A243 (alO) A244 (alO) y x " R x \ R RI 0 0 0 A245 (alO) A246 (alO) A247 (alO) A248 (alO) y X, "' X" y X"Rl X 0 WO 2011/015241 PCT/EP2009/060168 447 A249 (alO) A250 (alO) A251 (alO) A252 (alO) 11 Y XXX"R1 X, A253 (alO) A254 (alO) A255 (alO) A256 (alO) Xl Rl X o0 0 00 A257 (alO) A2582(alO) A2593(alO) A2604(alO) 0 o 0 A2615(alO) A2626(alO) A2637(alO) A2648(alO) A2659(alO) A2660(alO) A27 (alO) A2682(alO) WO 2011/015241 PCT/EP2009/060168 448 Rly Yl y~ y :1: x 0 X 0 I ~ R 51 0 0II A273 (alO) A274 (alO) A275 (alO) A276 (alO) 0 /Rl 0 /Y o x R 51 ,X 0 IxI I A277 (alO) A278 (alO) A279 (alO) A280 (alO) 0 x I I I 5 A281 (alO) A282 (alO) A283 (alO) A284 (alO) y Y Y 00 X 0 0: A285 (alO) A286 (alO) A287 (alO) A288 (alO) Y\ Y\ / 1R yR 0 0 0 0 Io A "x x x I I I A280 (alO) A290 (alO) A291 (alO) A292 (alO) WO 2011/015241 PCT/EP2009/060168 449 O R A293 (a1 ) 2 4(1 )A 9 a0) 2 6(1 xN O ~ ~ RN ' 1 II II A293 (alO) A294 (alO) A295 (alO) A296 (alO) X RR4 ' Rl00 yR A297 (alO) A298 (alO) A299 (alO) A300 (alO) R3 R3 4 R1R3 Rx4 A301 (alO) A302 (alO) A303 (alO) A304 (alO) 346 4 X Rx x A305 (alO) A306 (alO) A307 (alO) A308 (alO) R 41R 34 R l R 34 N X, y X" y X, N x, - - - R 36 0 0 A309 (alO) A310 (alO) A311 (alO) A312 (alO) WO 2011/015241 PCT/EP2009/060168 450 R- R34R R 34 R lR 34 y XN -N Y X, y X, y X, o R 36 o 0 0 A313 (alO) A314 (alO) A315 (alO) A316 (alO) y Rl R 3 RlR 341 R RlR 34 yy X y N, o 0 0 A317 (alO) A318 (alO) A319 (alO) A320 (alO) Rl R 34 R 1 R 34 R3R R4 o0~ A321 (alO) A322 (alO) A323 (alO) A324 (alO) R A325 (alO) A326 (alO) A327 (alO) A328 (alO) Rl Rl R 00 A329 (alO) A330 (alO) A331 (alO) A332 (alO) WO 2011/015241 PCT/EP2009/060168 451 -R 3 lyR 34 R 34 X X 0 0 0 0' A333 (alO) A334 (alO) A335 (alO) A336 (alO) R 34 y R 34 lR yR 1 \ ~ - Y y ~R 34 0 44 x x, 0 0 0 3 0 A337 (alO) A338 (alO) A339 (alO) A340 (alO) R 34 R"'Rl R3 yR 00 A341 (alO) A342 (alO) A343 (alO) A344 (alO) R 34 4 x R 34 - R 3 xX 00 0 A345 (alO) A346 (alO) A347 (alO) A348 (alO) R 34 R R 34 1lyR3 R 36 ~ y 0. 0, 00 A349 (alO) A350 (alO) A351 (alO) A352 (alO) WO 2011/015241 PCT/EP2009/060168 452 R1 R 34 R1 Y\ R R34 II :y I R I " I A353 (alO) A354 (alO) A355 (alO) A356 (alO) R 34 N R1 R1 O N y 37X N1 3-' - '. X R 37 -N X R 1 ~ R 37 -N R1 0 0 A357 (alO) A358 (all) A359 (all) A360 (all) R1 R1 R 1 R 37 N R37 N N R 37 -N R37-N R1 / N , N X" , X, o 0 A361 (all) A362 (all) A363 (all) A364 (all) R 37 R 1 R3 NN R1 \ X'R1 X R1 N N1 0 N 0 x x O O0 A365 (all) A366 (all) A367 (all) A368 (all) R37 37 R37 R1 R37 N% N R 1 R\N N R13 O O 0 ( 0 7 ( l A369 (all) A370 (all) A371 (all) A372 (all) WO 2011/015241 PCT/EP2009/060168 453 N~R 37 N N N % N 0 A373 (a12) A374 (a12) A375 (a12) A376 (a12) R 37 R 37 Rl R N N N -N N-R37 N-R37 l_ I _NI _ ,X" 0 Ny X 0 1 0N X A377 (a12) A378 (a12) A379 (a12) A380 (a12) RlR 37 R 37 R 1 R N-R37 Nl INN "N R\ - N 0 xN I I A381 (a12) A382 (a12) A383 (a12) A384 (a12) -N I -- l I _- Ik N R 1 R 7 NNR 37 N N R, RN37 0 0 0 A385 (a12) A386 (al3) A387 (al3) A388 (al3) R 373 -R N\ N N N N R\, N N IX0 N X 0 N X A389 (al3) A390 (al3) A391 (al3) A392 (al3) WO 2011/015241 PCT/EP2009/060168 454 N 7IR3 R 1 R 37 R 37 Nl X N Xl A393 (a13) A394 (a13) A395 (a13) A396 (a13) R 1 R 37 R 3 7 o0 N' 0 / N'I R37-N ~N R 37 -N I I -I R1 X, N IX N IX X A397 (a13) A398 (a13) A399 (a14) A400 (a14) RlR 3 7 R 1 R 37 IR 37 Ri/N ,N R 37 N NlR -- NJ I .) - N.. x x N ,x 0o 0 0 A401 (a14) A4 02 (a14) A403 (a14) A404 (a14) R 37 R 37 R 1 R 37 R N37-~ N 0l I I- R IN 0 I A405 (a14) A406 (a14) A407 (a14) A408 (a14) - Rl R 37 -N - ~ NlR R 3 7 NIN N-R 37 N-R37 Ix 0 0 I A409 (a14) A410 (a14) A411 (a14) A412 (a14) WO 2011/015241 PCT/EP2009/060168 455 N N-R37 N Rl K'R 0 , 0 A413 (a14) A414 (al5) A415 (al5) A416 (al5) R 1 X" X" R1 X, A417 (al5) A418 (al5) A419 (al5) A420 (al5) y- N Y\ Y\ Rl N 0 0 A421 (al5) A422 (al5) A423 (al5) A424 (al5) /-yy R y N< N x N X" NX <N X" 0 A425 (al5) A426 (al5) A427 (al5) A428 (al5) N. NN N x, 0 x 0 0 A429 (al5) A430 (al5) A431 (al5) A432 (al5) WO 2011/015241 PCT/EP2009/060168 456 0 N 0: x5 0: x N l! A433 (al5) A434 (al5) A435 (al5) A436 (al5) l: N Y-\N 51 R1 51 R I A437 (al5) A438 (al5) A439 (al5) A440 (al5) N Rl N 0 o 0 I A441 (al5) A442 (al5) A443 (al5) A444 (al5) 0 -\0 Y --\ R 0 z NN 0 Ny A445 (al5) A446 (al5) A447 (al5) A448 (al5) o N=; 1iyR y-N y R 53 5 , X, 0 0 0 A449 (al5) A450 (a16) A451 (a16) A452 (a16) WO 2011/015241 PCT/EP2009/060168 457 y- R53 R 53 R Rl x x, X o0 00 A453 (a16) A454 (al16) A455 (al16) A456 (a16) N R5 R 53 / N A457 (a16) A458 (a16) A459 (a16) A460 (a17) 00 00 A461 (a17) A462 (a17) A463 (a17) A464 (a17) N~x i R 1 o0 A465 (a17) A466 (a17) A467 (a17) A468 (a17) N N1 XX 0 000 A469 (a17) A470 (a17) A471 (a17) A472 (a17) WO 2011/015241 PCT/EP2009/060168 458 R R Rl R1 x, , , X' X o 00 A477 (a17) A478 (a17) A479 (a17) A480 (a17) 00 N X 0 0 X 0 R 51 A481 (a17) A482 (a17) A483 (a17) A484 (a17) 0 N0 N x 0 N x 0 N x A485 (a17) A486 (a17) A487 (a17) A488 (a17) o0 N1 0 N1 A 0 0 N I I A489 (a17) A490 (a17) A491 (a17) A492 (a17) WO 2011/015241 PCT/EP2009/060168 459 A493 (a17) A494 (a17) A495 (a17) A496 (a17) A497 (a17) A498 (a17) A499 (a17) A500 (a17) RR34 R N RN 0 0 A501 (a17) A502 (a17) A503 (a17) A504 (a17) Rl R 34 R3 R 34 R R 34 0 x I A505 (a17) A506 (a17) A507 (a17) A508 (a17) RlI34[i 34 N34 N R 34 N i 0R R 3 o0 0 N 0 N A509 (a17) A510 (a17) A511 (a17) A512 (a17) WO 2011/015241 PCT/EP2009/060168 460 R R 30 R 3 4 R lN 34 Ri X N. x0 A513 (a17) A514 (a17) A515 (a17) A516 (a18) R 1 N ,N1 1 x" X" N11 N 0'0 A517 (a18) A518 (a18) A519 (a18) A520 (a18) N N.-' x" X, X NN 0'- 0 0 0' A521 (a18) A522 (a18) A523 (a18) A524 (a18) -' N ~N I N 0' 0' 0 0' A525 (a18) A52 6 (a18) A527 (a18) A528 (a18) N X, N x N A529 (a18) A530 (a18) A531 (a18) A532 (a18) WO 2011/015241 PCT/EP2009/060168 461 R 1 NN4 N 0, N R 1 0; N0',R I XI II x I A533 (a18) A534 (a18) A535 (a18) A536 (a18) aN N X N- X N1 0'~ A537 (a18) A538 (a18) A539 (a18) A540 (a18) N N 1 x x Rl0 oi 0o -- N -- N R - N NlN A549 (a18) A550 (a18) A551 (al18) A552 (a18) WO 2011/015241 PCT/EP2009/060168 462 R1 R1 R1 RNR N X, O0NXN N.. x I I A553 (a19) A554 (a19) A555 (a19) A556 (a19) RO RlR R1 N| o 0~ N X 0 0 N X N X N X A557 (a29) A558 (a29) A559 (a29) A560 (a29) N N 11 N -IN X X N X A561 (a29) A562 (a29) A563 (a29) A564 (a29) NR -lN~- R 1 R 1 N N l o N N~ N N~N x NN "I 0 A565 (a20) A566 (a2 0) A567 (a2 0) A568 (a20) N N I I, INN N N N N- X 0 N I 0 0 N X A569 (a20) A570 (a2 0) A571 (a20) A572 (a20) WO 2011/015241 PCT/EP2009/060168 463 0- N _- N "N N N 0 P 1NINI NX o RN~N N N X" N X" I 0 0 A577 (a20) A578 (a21) A579 (a21) A580 (a21) I 1 Rl0 N N iNq R ClN 1 N X" N 0z N -~N A581 (a21) A582 (a21) A583 (a21) A584 (a21) R 1 N R 0 N N X I p 00 ' N X jNN N-I N N- %NR N N N ~ -- 0' 0 x N - A589 (a22) A590 (a22) A5 91 (a22) A592 (a22) WO 2011/015241 PCT/EP2009/060168 464 N R 1 N R R N N N NN X N -x N X a K "o N X O A593 (a22) A594 (a22) A595 (a22) A596 (a22) Rl R1 Rl Rl N N N N N -N N N O N X N X N X 0 N X A597 (a22) A598 (a22) A599 (a22) A600 (a22) R1 R N RN R O N N X A601 (a22) A602 (a23) A603 (a23) A604 (a23) R 1 N N 1 R 1 N N R 1 N R NN N oN- 0 N N X N O N X N X 0 I ' A605 (a23) A606 (a23) A607 (a23) A608 (a23) R1 R RN R R R RX 0"'' X -1I 0 N 0 N x A609 (a24) A610 (a24) A611 (a24) A612 (a24) WO 2011/015241 PCT/EP2009/060168 465 R1 O O 3 8 R 1 A613 (a24) A614 (a24) A615 (a24) A616 (a24) R1 R1 R1 0 x R 38 38 X ' 0 0 A617 (a24) A618 (a24) A619 (a25) A620 (a25) R1R1 O1 xK R 38 X O R1 38 0 A621 (a25) A622 (a25) A623 (a25) A624 (a25) O1 R1 01 R18 R3 x''. X, A625 (a25) A626 (a25) B is selected from the divalent building blocks B1-B21 shown in Table 11, below which are based on optionally substituted 5 cyclic secondary amines carrying a moiety of type -CHR 3 -LG, wherein LG is a suitable leaving group that can be replaced by the nucleophilic groups of building blocks A thus forming an ether (-0-) or a thioether (-S-) linkage between building blocks of type A and B; 10 WO 2011/015241 PCT/EP2009/060168 466 Table 12: Embodiments of Linker C R 4 R 5 0 R4 R 7O R4 R 9 R4 R 5 0 R4 R 7 R 3 R 9 I | 11 1 11 1 | | | || I | | --- N-C- C-N-C---C-N-C--U--- --- N-C- C-N-C--C-Z-C-U-- I I I I I H I RR 8 RL R 10 R 6 R 8 1 0-1 ~-1 0-1 C1 C2 R 4 R 5 R 3 R 7 OR 4 R 9 4 5 R4 R 7 R 12 R 9 R R R 0 R R9I 1 11 1 1 1 I I I 1 11 1 1 --- N-C- C-N-C--Cr-C-U--- --- N-C-C-Z-C-C-N-C-U--- I- - U I H I R6 R R13 Rio R6R 1 R8 1 io 0 0-1 C3 C4 R 4 R 5 R 12 R 7 0 R 4 R 9 R 4 R 5 R 3 R 7 R 3 R 9 | | I I|| I |I | | | | | --- N-C-C---C-C-C-N-C-U--- --- N-C-C-Z-C-C-Z-C-U-- I I I | | | | | R6 R13 R8 Rio R 6 H R 8 H Rio C5 C6 R 4 R 5 R 1 4 0 R 4 R 7 R 1 6 R4 R 5 R 14 R 4 R 16 R 7 1 1 1 | | 1 1 | 1 | 1 | | 1 | 1 --- N-C-C--C-N-C--C---U--- --- N-C- C--C-N- C--C-U-- I I I I I I I I R 6 R 1 5 R 8 R 1 7 R 6 R 1 5 R 1 7 R 8 t 0-1 0-1 t C7 C8 R 4 R 14 R 5 0 R4 R 7 R 1 6 R 4 R 14 R 5 0 R 4 R 1 6 R 7 | | | I|| | | |I | |l || i I I --- N-C-C--C-N-C- -C- -- U--- --- N-C-C-C-N- C- -C-U-- I I I | | 1 | | R 15 R 6 R 8 R 17 R 15 R 6 R 1 7 R 8 0-1 C9 C10 R 4 R 5 R 1 4 R 3 R 16 R 7 R 4 R 5 R 14 R 3 R 7 R 1 6 I 1 | 1 | 1 1 | 1 | 1 1 --- N-C- C--C-Z- C--C-U --- --- N-C-C-C-Z-C- C--U-- I 1 1 | 8 6 1 I I I R 6 R 1 5 H R R R R 15 H R 8 R 1 7 0-1 t u C1l C12 WO 2011/015241 PCT/EP2009/060168 467 R 4 R 1 4 R 5 R 3 R 16 R 7 R 4 R 1 4 R 5 R 3 R 7 R 1 6 I 1 1 | | | 1 | 1 | 1 1 --- N-C-C-C-Z- C--C-U--- --- N-C-C-C-Z-C-C--U-- R 1 5 R H R1R 15 R H R R 1 7 u u C13 C14 R 4 R 5 R 1 4 R 1 2 R 16 R 7 R 4 R 5 R 1 4 R 12 R 7 R 16 I I | I | | | | I 1 --- N-C- C--C---C--C--C-U--- --- N-C-C-C---C-C-C--U-- R 6 R 1 5 R 13 R 1 7 R 8 R 6 R 1 5 R 1 3 R 8 R 1 7 0-1 t u C15 C16 R 4 R 1 4 R 5 R 1 2 R 16 R 7 R 4 R 14 R 5 R 12 R 7 R 16 I I |I I I I | | I 1 --- N-C-C-C---C- C--C-U--- --- N-C-C-C---C-C-C--U-- R 1 5 R 6 R 1 3 R 1 7 R 8 R 15 R 6 R 1 3 R 8 R 1 7 u u C17 C18 R 4 R 5 R 14 R 14 0 R 4 R 7 R 16 R 4 R 5 R 14 R 14 0 R 4 R 16 R 7 R 16 | | | | | | | | 1 | | | | | | | | | 1 --- N-C-C-C--C-N-C- C- U --- N-C-C-C-C-N-C-C- C- U-- I | | | I | | | | | | R 6 R 15 R 15 R 8 R 17 R 6 R 15 R 15 R 17 R 8 R 17 t _ 0 1 0-1 C19 C20 R 4 R 5 R 14 R 14 0 R 4 R 16 R 7 R 4 R 14 R 5 R 14 0 R 4 R 7 R 16 I I I I I I | 1 | | | | | | | | | 1 --- N-C-C-C-C-N--C--C-U--- --- N-C-C-C--C-N-C- C- U-- 15 R6 15 8 17 I I R 6 R 15 R 15 R 17 R 8 R 15 R 6 R 15 R 8 R 17 t 0-1 C21 C22 R 4 R 14 R 5 R 14 0 R 4 R 16 R 7 R 16 R 4 R 14 R 5 R 14 0 R 4 Ri 6 R 7 I I I | | I | | | | | | | | | 1 | --- N-C-C-C-C-N-C-C- C U--- --- N-C-C-C-C-N- C--C-U-- 1 I I I I I | | | | | R 15 R 6 R 15 R 17 R 8 R 17 R 15 R 6 R 15 R 17 R 8 0-1 u C23 C24 WO 2011/015241 PCT/EP2009/060168 468 R 4 R 14 R 14 R 5 0 R 4 R 7 R 16 R 4 R 14 R 14 R 5 0 R 4 R 16 R 7 R 16 I I I | | | | | 1 | | | | | | | | | 1 --- N-C-C-C--C-N-C- C---U --- N-C-C-C-C-N-C-C--C--U-- I I I I I I I I I I I R 15 R 15 R 6 R 8 R 17 R 15 R 15 R 6 R 17 R 8 R 17 t 0-1 C25 C26 R 4 R 14 R 14 R 5 0 R 4 R 16 R 7 R 4 R 5 R 14 R 14 R 3 R 7 R 16 I I I I 1 II | | 1I | | | | | --- N-C-C-C-C-N--C--C-U--- --- N-C-C-C-C-Z-C--C--U-- I I I I I I I I I I I R 15 R 15 R 6 R 17 R 8 R 6 R 15 R 15 H R 8 R 17 u t C27 C28 R 4 R 5 R 14 R 14 R 3 R 16 R 7 R 16 R 4 R 5 14 14 3 R 16 R 1 6 7 I I I I I I I IR4 R R1 R1 R3 16 16 7 --- N-C-C-C-C-Z-C-C- C- -U--- __ I I I I I I I I 6 RI 5 I 1 I I I I --- N-C-C-C-C-Z-C-C-C-U-- R6 15 15 R1 R8 R17I I I I I I I RR R R 6 R 15 R 15 H R 17 R 17 R 8 0-1 C29 C30 R 4 R 14 R 5 R 14 R 3 R 7 R 16 R 4 R 14 R 5 R 14 R 3 R 16 R 7 R 16 I I I I I I I I I I I I I I I --- N-C-C-C-C-Z-C-C--U--- --- N-C-C-C-C-Z-C-C- C--U-- I I I I I I I I I I I I I R 15 R 6 R 15 H R 8 R 17 R 15 R 6 R 15 H R 17 R 8 R 17 u 0-1 C31 C32 R 4 R 14 R 5 R 14 R 3 R 1 6 R 1 6 7 R 4 R 14 R 14 R 5 R 3 R 7 R 16 R R R RI I I I I I I I I I I I I I I --- N-C-C-C-C-Z-C- C--U-- --- N-C-C-C-C-Z-C-C-C-U--- 15 1 15 1 6 1I 11 R 15 R 6 R 15 H 17 17 8 R 15 R 15 R 6 H R 8 R 17 t C33 C34 R 4 R 1 4 R 14 R 5 R 3 R 16 R 7 16 4 1 4 14 R 5 3 R 16 R 16 R 7 I I I I I I I IR4 R 4R 4R R3 16 16 7 --- N-C-C-C-C-Z-C-C- C--U--- __ I I I I I I I I I I I I I I --- N-C-C-C-C-Z-C-C-C-U-- R 15 R 15 R 6 H R 17 R 8 R 17 I I I I I I I - iR 15 R 15 R 6 H R 17 R 17 R 8 0-1 C35 C36 R 4 R 5 R 14 R 14 R 12 R 7 R 16 R 4 R 5 R 14 R 14 R 12 R 16 R 7 Ri 6 I | | I I | | I | | |I | | --- N-C-C-C-C---C-C- C- -U--- --- N-C-C-C-C--C-C-C- C- -U-- I I I I I I I I I I I R 6 R 1 5 R 15 R 13 R 8 R 17 R 6 R 15 R 15 R 13 R 17 R 8 R 17 t 0-1 WO 2011/015241 PCT/EP2009/060168 469 C37 C38 R 4 R 5 R 14 R 14 R 12 R 16 R 16 7 R 4 R 14 R 5 R 14 R 1 2 R 7 R 16 R R R R R R RI I I I I I I I I I I I I --- N-C-C--C--CC--C C U-- --- N-C-C-C-C-C-C-C-C-U--- I I I I I R 6 R 15 R 15 R 13 R 17 R 1 7 R 8 R 15 R 6 R 15 R 13 R 8 R 17 u C39 C40 R 4 R 14 R 5 R 14 R 12 R 1 6 R 7 R 16 R 4 R 14 R 5 R 1 4 R 1 2 R 16 R 1 6 R 7 --- N-C-C--C--CC -C--C C U--- I I I I I I I -- - C C C - -I I --- N-C-C- C- C -C-C- C-C- U-- R 15 R 6 R 15 R 13 R 1 7 R 8 R 17 15 I I 1 R 5 RR 15 R 13 R 17 R 17 1 8 0-1 C41 C42 R 4 R 14 R 14 R 5 R 12 R 7 R 16 R 4 R 14 R 14 R 5 R 12 R 16 R 7 R 16 I | | I I | | I | | I I | | --- N-C-C-C--CC--C -C- U--- --- N-C-C-C-C=C-C-C- C -U-- | | | I | |I | |I I I I R 15 R 15 R 6 R 13 R 8 R 1 7 R 15 R 15 R 6 R 13 R 1 7 R 8 R 17 t 0-1 C43 C44 R 4 R 5 R 14 0 R 4 R 7 R 4 R 14 R 14 R 5 R 12 R 16 R 16 R 7 I I | || | | I I I I I I I --- N-C--C--C-N-C--U-- --- N-C-C-C-C=C-C--C-C-U--- I I I R 15 R 15 R 6 R 13 R 17 R 1 7 R 8 R 6 R 15 8 3-5 _ 0-1 C45 C46 R 4 R 1 4 R 5 0 R 4 R 7 R 4 R 5 R 14 R 3 Ri 6 R 7 | | 1 | | 1 1 1 | | 1 | 1 --- N--C--C--C-N-C--U--- --- N-C- C--C-Z- C--C-U-- I I 1 I | | | | R 1 5 R 6 R 6 R 1 5 H R17 R 3-5 _ 3-5 t C47 C48 R 4 R 5 R 14 R 12 R 16 R 7 R 4 R 5 R 14 R 4 0 R 4 R 7 R 16 --- N-C- C--C---C- C--C-U--- --- N-C- C--N-C-N-C- C--U-- R 6 R 15 R 13 R 1 7 R 8 R 6 R 1 5 R 8 R 1 7 3-5 t 1-5 1-5 C49 C50 WO 2011/015241 PCT/EP2009/060168 470 R 4 R 14 R 5 R4 0 R4 R 7 R 16 R 4 R 14 R 5 R4 0 R 4 R 16 R 7 |I I I | | | I | | I 1 I 1 | --- N--C--C-N-C-N-C--C--U--- --- N--C--C-N-C-N--C-C-U-- I II I | |I R 15 R 6 R 8 R 17 R 15 R 6 R 17 R 8 1-5 1-5 1-5 1-5 C51 C52 R 4 R 5 R 1 4 R 4 0 R 4 R 1 6 R 7 --- N-C--C--N-C-N--C--C-U-- I I I I R 6 R 1 5 R 17 R 8 1-5 1-5 C53 R 4 R 5 R 1 4 0 R 4 R 7 R 1 6 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N-C--C--C-N-C--C--C-N-C-U-- I I I I I R 6 R 15 R 8 R 17 Rl0 t u C54 R 4 R 14 R 5 0 R 4 R 7 Ri 6 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N--C--C-C-N-C--C--C-N-C-U-- I I I I I R 1 5 R 6 R 8 R 1 7 Rl0 u u C55 R 4 R 1 4 R 5 0 R 4 R 16 R 7 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N--C--C-C-N--C--C-C-N-C-U-- I I I I I R 15 R 6 R 1 7 R 8 Rl0 u u C56 R 4 R 5 R 14 0 R 4 R 16 R 7 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N-C--C--C-N--C--C-C-N-C-U-- I I I I I R 6 R 15 R 1 7 R 8 Rl0 t u C57 WO 2011/015241 PCT/EP2009/060168 471 R 4 R 5 R 14 R 3 R 7 R 16 0 R4 R 9 I I I I I I I I I I --- N-C--C--C-Z-C--C--C-N-C-U-- I I | 1 I | R 6 R 1 5 H R 8 R 17 Rl0 t u C58 R 4 R 14 R 5 R 3 R 7 R 6 0 R4 R 9 I I I I I I I I I I --- N- C--C-C-Z-C--C--C-N-C-U-- R 1 5 R 6 H R 8 R 1 7 Rl0 u u C59 R 4 R 14 R 5 R 3 R 16 R 7 0 R4 R 9 I I I I I I I I I I --- N--C--C-C-Z--C--C-C-N-C-U-- R 15 R 6 H R 1 7 R 8 u u C60 R 4 R 5 R 14 R 3 R 16 R 7 0 R4 R 9 I I I I I 1 | | | 1 --- N-C--C--C-Z--C--C-C-N-C-U-- I I | | 1 I R 6 R 15 H R 17 R 8 Rl t u C61 R 4 R 5 R 14 0 R 4 R 7 R 16 R 3 R 9 I I 1 | | | 1 | 1 1 --- N-C--C--C-N-C--C--C-Z-C-U-- I I 1 I | | R 6 R 15 R 8 R 1 7 H t u C62 R 4 R 14 R 5 0 R4 R 7 R 16 R 3 R 9 I I 1 | | | 1 | 1 1 --- N--C--C-C-N-C- C--C-Z-C-U-- R 15 R 6 R 8 R 1 7 H u u C63 WO 2011/015241 PCT/EP2009/060168 472 R 4 R 14 R 5 0 R4 R 16 R 7 R 3 R 9 I 1 1 | | | 1 1 1 1 --- N--C--C-C-N--C--C-C-Z-C-U-- R 15 R 6 R 1 7 R 8 H u u C64 R 4 R 5 R 14 0 R 4 R 16 R 7 R 3 R 9 I I 1 | | | 1 1 1 1 --- N-C--C--C-N--C--C-C-Z-C-U-- I I | 1 | | R 6 R 15 R 1 7 R 8 H t u C65 R 4 R 5 R 14 R 3 R 7 R 16 R 3 R 9 I I I I I I I I --- N-C--C--C-Z-C--C--C-Z-C-U-- I I | 1 I | | R 6 R 15 H R 8 R 17 H t u C66 R 4 R 14 R 5 R 3 R 7 R 16 R 3 R 9 I I I I I I I I --- N- C--C-C-Z-C--C--C-Z-C-U-- R 1 5 R 6 H R 8 R 1 7 H u u C67 R 4 R 14 R 5 R 3 R 6 R 7 R 3 R 9 I I I I I I I I --- N- C--C-C-Z--C--C-C-Z-C-U-- | 1 6 1 1 8 1 R 15 R 6 H R 17 R 8 H Rl0 u u C68 R 4 R 5 R 14 R 3 R 16 R 7 R 3 R 9 I I I I I I I I --- N-C- -C- -C-Z- -C- -C-C-Z-C-U-- I I | | 1 | | R 6 R 15 H R 17 R 8 H Rl0 t u C69 WO 2011/015241 PCT/EP2009/060168 473 R 4 R 5 R 14 0 R4 R 7 R 16 R 1 2 R 9 I I I || | | | I --- N-C--C--C-N-C--C--C=C-C-U-- R 6 R 1 5 R 8 R 17 R 1 3 R 1 0 t u C70 R 4 R 14 R 5 0 R4 R 7 R 16 R 12 R 9 | | | || | | |I I --- N--C--C-C-N-C--C--C=C-C-U-- I I I | I R 15 R 6 R 8 R 1 7 R 13 R 10 u u C71 R 4 R 14 R 5 0 R 4 R 16 R 7 R 12 R 9 I I I I I I 1 1 4 --- N--C--C-C-N--C--C-C=C-C-U-- I I | | I R 15 R 6 R 1 7 R 8 R 13 R 10 u u C72 R 4 R 5 R 14 0 R 4 R 16 R 7 R 12 R 9 I I I I I I 1 1 4 --- N-C- -C--C-N- -C--C-C=C-C-U-- R 6 R 15 R 1 7 R 8 R 13 R 10 t u C73 R 4 R 5 R 14 R 1 2 R 7 R 16 0 R 4 R 9 --- N-C--C--C=C-C- C--C-N-C-U-- 1 |I I | | R 6 R 15 R 13 R 8 R 17 Rl0 t u C74 R 4 R 14 R 5 R 12 R 7 R 6 0 R4 R 9 I 1 1 4 1 1 | | | 1 --- N- -C--C-C=C-C- C--C-N-C-U-- I I I | |I R 1 5 R 6 R 13 R 8 R 1 7 Rl0 u u C75 WO 2011/015241 PCT/EP2009/060168 474 R 4 R 14 R 5 R 1 2 Ri 6 R 7 0 R4 R 9 I 1 1 4 1 1 | | | 1 --- N--C--C-C=C- C--C-C-N-C-U-- I I I I | R 15 R 6 R 13 R 17 R 8 Rl0 u u C76 R 4 R 5 R 14 R 1 2 R 16 R 7 0 R4 R 9 I I 1 4 1 1 | | | 1 --- N-C--C--C=C--C--C-C-N-C-U-- R 6 R 15 R 13 R 17 R 8 Rl0 t u C77 R 4 R 5 R 1 4 R 1 2 R 7 R 16 R 3 R 9 | | |I I I | | --- N-C--C--C=C-C--C--C-Z-C-U-- 1 |I I | | | R 6 R 15 R 1 3 R 8 R 1 7 H t u C78 R 4 R 14 R 5 R 12 R 7 Ri 6 R 3 R 9 I 1 1 I 1 | --- N--C--C-C-C-C--C--C-Z-C-U-- I I I | | | R 15 R 6 R 13 R 8 R 1 7 H u u C79 R 4 R 1 4 R 5 R 1 2 R 1 6 R 7 R 3 R 9 I 1 1 I I I --- N--C--C-C-C- C--C-C-Z-C-U-- I I I I | | R 15 R 6 R 1 3 R 1 7 R H R C80 R 4 R 5 R 14 R 1 2 R 1 6 R 7 R 3 R 9 I I I I | | 1 --- N-C--C--C=C- -C--C-C-Z-C-U-- R 6 R 15 R 1 3 R 17 R 8 H t u C81 WO 2011/015241 PCT/EP2009/060168 475 R 4 R 5 R 1 4 R 1 2 R 7 R 1 6 R 1 2 R 9 I I I I | I --- N-C--C--C=C-C--C--C-C-C-U-- 1 |I I | I R 6 R 15 R 13 R 8 R 17 R 13 R 10 t u C82 R 4 R 14 R 5 R 1 2 R 7 Ri 6 R 12 R 9 I I | I | I --- N--C--C-C-C-C--C--C=C-C-U-- I I I | |I R 15 R 6 R 13 R 8 R 1 7 R 13 R 1 0 u u C83 R 4 R 1 4 R 5 R 1 2 Ri 6 R 7 R 1 2 R 9 I I | I |I I --- N--C--C-C=C- C--C-C=C-C-U-- I I I I I R 15 R 6 R 13 R 17 R 8 R 13 R 10 u u C84 R 4 R 5 R 14 R 1 2 R 1 6 R 7 R 1 2 R 9 I I I I |I I --- N-C--C--C=C- -C--C-C=C-C-U-- R 6 R 15 R 13 R 17 R 8 R 13 R 10 t u C85 R 4 R 5 R 14 R 3 R 7 R 1 6 R 1 2 R 9 I I I | | |I I --- N-C--C--C-Z-C--C--C=C-C-U-- R 6 R 15 H R 8 R 17 R 13 R 10 t u C86 R 4 R 14 R 5 R 3 R 7 R 16 R 12 R 9 I I | | | | I --- N--C--C-C-Z-C--C--C=C-C-U-- I I I I | I R 1 5 R 6 H R 8 R 1 7 R 13 R 10 u u C87 WO 2011/015241 PCT/EP2009/060168 476 R 4 R 14 R 5 R 3 R 16 R 7 R 12 R 9 I I | | | | I --- N--C--C-C-Z--C--C-C=C-C-U-- I I | | I >I R 15 R 6 H R 1 7 R 8 R 1 3 R 10 u u C88 R 4 R 5 R 14 R 3 R 16 R 7 R 12 R 9 I I I | | | I --- N-C--C--C-Z--C--C-C=C-C-U-- S | | | 18 > R 6 R 15 H R 17 R R 13 R 10 t u C89 R 4 R 5 R 14 R 4 0 R 7 R 16 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N-C--C--N-C-C--C---C-N-C--U-- I I I I I R 6 R 1 5 R 8 R 1 7 Rl0 1-5 t _ _ 1 C90 R 4 R 14 R 5 R 4 0 R 7 R 16 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N--C--C-N-C-C--C---C-N-C--U-- I I I I I R 15 R 6 R 8 R 1 7 Rl0 1-5 t _ 1 C91 R 4 R 14 R 5 R 4 o R 16 R 7 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N--C--C-N-C- C--C--C-N-C--U-- I I I I I R 15 R 6 R 1 7 R 8 Rl0 1-5 t __ 1 C92 R 4 R 5 R 14 R 4 0 Ri 6 R 7 0 R 4 R 9 I I I | | | | 1 | | | 1 --- N-C--C--N-C--C--C--C-N-C--U-- I I I I I R 6 R 1 5 R 17 R 8 Rl0 1-5 t __ 1 C93 WO 2011/015241 PCT/EP2009/060168 477 R 4 R 5 R 14 R 7 R 16 0 R4 R 9 I I I I I I I I I --- N-C--C--S-S-C--C---C-N-C--U-- I I I I I R 6 R 1 5 R 8 R 1 7 Rl0 u t 0-1 C94 R 4 R 14 R 5 R 7 R 16 0 R4 R 9 I I I I 1 | | | 1 --- N--C--C-S-S-C--C---C-N-C--U-- I I I I I R 1 5 R 6 R 8 R 1 7 Rl0 u t 0-1 C95 R 4 R 14 R 5 R 16 R 7 0 R4 R 9 I I I I 1 | | | 1 --- N- -C--C-S-S--C--C--C-N-C--U-- I I I I I R 15 R 6 R 17 R 8 Rl0 0-1 C96 R 4 R 5 R 1 4 R 16 R 7 0 R4 R 9 I I I I 1 1 1 1 1 --- N-C--C--S-S--C--C--C-N-C--U-- I I I I I R 6 R 1 5 R 17 R 8 Rl0 L t 0-1 C97 R 4 R 5 R 1 4 0 0 R 7 R 16 0 R 4 R 9 I I 1 | | | | I 1 | | | 1 --- N-C--C--C-C-C--C---C-N-C--U-- I I I I I R 6 R 1 5 R 8 R 1 7 Rl0 u t 0-1 C98 R 4 R 14 R 5 0 0 R 7 R 16 0 R 4 R 9 I I 1 | | | | I 1 | | | 1 --- N--C--C-C-C-C- C---C-N-C--U-- I I I I I R 1 5 R 6 R 8 R 1 7 Rl0 u t - - 0-1 WO 2011/015241 PCT/EP2009/060168 478 C99 R 4 R 14 R 5 0 0 R 1 6 R 7 0 R 4 R 9 I I 1 | | | | I 1 | | | 1 --- N--C--C-C-C--C--C--C-N-C--U-- I I I I I R 15 R 6 R 17 R 8 R10 u t 0-1 C100 R 4 R 5 R 1 4 0 0 R 1 6 R 7 0 R 4 R 9 I I | | | | | | 1 | | | 1 --- N-C--C--C-C--C--C--C-N-C--U-- I I I I I R 6 R 1 5 R 17 R 8 R10 L t 0-1 C101 R' is H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower 5 heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 8 R1 9 ) qOR 20 ; - (CR R 19) qNR 4 R"; - (CR' 8 R' 9 ) qNR 4 COOR 21 ; - (CR R 9) qNR 4 COR 22 ; - (CR R 9) qNR 4CONR4 R"; - (CR R 9) qNR 4 SO 2 R 23 ; - (CR' 8 R' 9 ) qNR 4 SO 2 NR 4 R"; - (CR' 8 R' 9 ) qCOOR 21 ; - (CR' 8 R' 9 ) qCONR 4 R"; - (CR' 8 R' 9 ) qSO 2 NR 4 R"; 10 - (CR' 8 R' 9 ) qPO (OR 21 ) 2; - (CR 8 R1 9 ) gCOR 22 ; - (CR' 8 R' 9 ) qSO 2 R; 23 - (CR' 8 R' 9 ) qOSO 3 R 1 ; - (CR 8 R1 9 ) qR 24 ; - (CR 8 R1 9 ) qR 25 ; or - (CR 8 R1 9 ) qR 26 ; R2 is H; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 15 - (CR R 19) qOR 2 0 ; - (CR R 9) qNR 4 R"; - (CR' 8 R' 9 ) qNR 4 COOR 21 ; - (CR' 8 R' 9 ) qNR 4 COR 22 ; - (CR 8 R1 9 ) qNR 4 CONR 4 R"; - (CR' 8 R' 9 ) qNR 4 SO 2 R 23 ; - (CR' 8 R' 9 ) qNR 4 SO 2 NR 4 R"; - (CR' 8 R' 9 ) qCOOR 2 1 ; - (CR' 8 R' 9 ) qCONR 4 R"; - (CR R 9) qSO 2 NR 4 R"; - (CR' 8 R' 9 ) qPO (OR 21 ) 2; - (CR 8 R 9 ) qCOR 22 ; - (CR' 8 R' 9 ) qSO 2 R 2 3 ; - (CR 8 R1 9 ) qR 24 ; - (CR 8 R1 9 ) qR 2 5 ; or - (CR 8 R1 9 ) qR 26 ; 20 R 3 is defined as in claim 1; R 4 is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; or a suitable N-protecting group; WO 2011/015241 PCT/EP2009/060168 479 R , R 7 and R 9 are independently defined as: H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower 5 heteroarylalkyl; - (CR R 19) OR 20 ; - (CR"R 9) NR 4 R"; - (CR"R' 9 ) sNR 4 COOR 2 1 ; - (CR"R 9) NR 4COR - (CR1 8 R' 9 ) sNR 4 CONR 4 R"; - (CR"R' 9 ) sNR 4 SO 2 R 2 3 ; - (CR"R19) sNR 4 SO 2 NR 4 R"; - (CR"R19) qCOOR 2 1 ; - (CR'"R' 9 ) qCONR 4 R"; - (CR"R19) qSO 2 NR 4 R"; - (CR'"R' 9 ) qPO (OR 2 1 ) 2; - (CR' 8 R' 9 ) qCOR 2 2 ; 10 - (CR"R19) qSO 2 R 23 ; - (CR 8 R 9 ) qR 24; - (CR 8 R 9 ) qR 25 ; or - (CR 8 R 9 ) qR 2 6 ; R , R 8 and R 10 are independently defined as: H; CF 3 ; or lower alkyl; 15 R" is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; a suitable protecting group; - (CR R19) rOR 2 0 ; - (CR R 9) rNR 4 R 2 7 ; - (CR'"R' 9 ) rNR 4 COOR; 2 1 - (CR'"R1 9 ) rNR 4 CONR 4 R 2 7 ; - (CR"R 9) rNR 4 SO 2 R 2 ; - (CR'"R' 9 ) rNR 4 SO 2 NR 4 R; 2 7 20 - (CR"R19) qCOOR 21 ; - (CR"R19) qCONR4 R ; - (CR' 8 R 9 ) qCOR 2 ; - (CR"R19) qSO 2 R 2 3 ; - (CR"R1 9 ) qSO 2 NR 4 R 27 ; - (CR1 8 R1 9 ) qR 24 ; - (CR1 8 R 9 ) R 25 ; or - (CR1 8 R1 9 ) qR 26 ; 25 R and R1 3 are independently defined as H; or lower alkyl; R 14 and R1 6 are independently defined as: H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower 30 heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR R 19) sOR 20 ; - (CR"R 9) sNR 4 R"; - (CR'"R' 9 ) sNR 4 COOR 2 1 ; - (CR"R19) sNR 4COR ; - (CR"R 9 ) sNR 4 CONR 4 R"; - (CR'"R' 9 ) sNR 4 SO 2 R; 2 3 - (CR'"R1 9 ) qCOOR 2 1 ; - (CR'"R' 9 ) qCONR 4 R"; or - (CR'"R1 9 ) qCOR 2 2 ; 35 WO 2011/015241 PCT/EP2009/060168 480 R1 5 and R1 7 are independently defined as: H; CF 3 ; lower alkyl; R8 is H; F; CF 3 ; lower alkyl; lower alkenyl; lower 5 cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29R ) sOR 3 ; - (CR 29R ) sNR R ; - (CR 29 R 30 ) NR 2 "COOR 2 1 ; -(CR 29 R3 )NR 2 COR; - (CR 29 R 30 ) NR 2 CONR 2 "R 3 1; -(CR 29 R 30 ) NR 28 SO 2 R; 23 -(CR 29 R 30 ) NR SO 2 NR R 9; -(29 30 28 31 R21S 2N 8R3 10 - (CR 29 R 3 0 ) qCOOR 2 1 ; - (CR 29 R 30 ) qCONR 2 "R 3 1 ; - (CR 29R ) qSO 2 NR R ; - (CR"R ) PO (OR") 2; - (CR"R") COR' 1 ; - (CR"R") SO 2 R"; -(CR 29R3 )qR 24 ; - (CR 29R3 )qR ; or - (CR 29 R 3 0 )qR2; R 19 is H; CF 3 ; or lower alkyl; 15 R is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29R ) rOR 3 ; - (CR 29R ) rNR R ; - (CR 29 R 30 ) rNR 2 "COOR; 2 1 20 - (CR 29R3 ) rNR "COR 1; - (CR 29 R 30 ) rNR CONR R ; - (CR 29 R 30 ) rNR 2 8 SO 2 R; 2 3 - (CR 29R ) qCOOR 21 ; - (CR 2 9 R 30 ) qCONR 2 R 31 ; - (CR R ) qSO 2 NR R3; - (CR 29R ) qCOR 31 ; - (CR 29 R 3 0 ) qSO 2 R 23 ; - (CR 29 R 3 0 ) qR 24 ; - (CR 29 R 3 0 ) qR 25 ; or - ( CR29R3 ) R26; 25 R and R 23 are as defined in claim 1; R is lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 30 - (CR 29R ) sOR 31 ; - (CR 29R ) sNR R ; - (CR 29 R 30 ) sNR 2 "COOR 2 1 ; 29 30) 28 3; 2 3) p2 C N 28" 31 (R2930 NR8S 2R3 - (CRR ) sNR "COR1; - (CR 2 9 R 30 ) SNR 2 CONR R1; - (CR 2 9 R 30 ) NR 2 SO 2 R 2 ; - (CR 2 9 R 30 ) sCOOR 2 1 ; - (CR 2 9 R 30 ) sCONR 2 "R 3 1 ; - (CR 29R ) sSO 2 NR R 1; - (CR 2 9 R 30 ) tCOR 31 ; - (CR 29 R 3 0 ) sSO 2 R 23 ; - (CR 29 R 3 0 ) tR 24 ; - (CR 29 R 3 0 ) tR 25 ; or - (CR 29 R 3 0 ) tR 26 ; 35 R 24, R' 25 R, 26 R 27 and R 2 " are as defined in claim 1; WO 2011/015241 PCT/EP2009/060168 481 R29 is H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 5 - (CR R ) sOR 31 ; - (CR R ) sNR R ; - (CR 32 R 33 ) sNR 28 COOR 2 1 ; - (CR R ) sNR "COR 1; - (CR 32 R 33 ) SNR 2 CONR R ; - (CR 32 R 33 ) sNR 28 SO 2 R; 23 - (CR 32 33 ) qCOOR 21 ; - (CR 32 R 33 ) qCONR 2 "R 31 ; - (CR R ) qSO 2 NR R 3; - (CR 32 33 ) qPO (OR 21 ) 2; - (CR R ) qCOR 31 ; - (CR R ) qSO 2 R 2 3 ; - (CRR 32 R 3 ) qR 31 ; 10 R 30 and R 33 are H; CF 3 ; or lower alkyl; R 3 and R 3 2 are as defined in claim 1; 15 R 34 and R 3 5 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29 R 3 0 ) qOR 3 ; - (CR 29 R 3 0 ) qNR 28 R; 31 20 - (CR 2 9 R 30 ) qNR "COOR 2 1 ; - (CR 29R ) qNR 2 "COR 31 ; - (CR 29 R 30 ) qNR 2 "CONR2 R; -(CR 29R )q NR S0 2 R 2 3 ; -(CR 29R3 ) qCOOR 2 1 ; - (CR R ) qCONR R 1; - (CR 29 R3 ) qSO 2 NR R ; - (CR 29 R 30 ) qCOR 31 ; - (CR R ) qSO 2 R 23 ; or - (CR 29 R 30 ) qR 31 ; 25 R 3 6 is as defined in claim 1; R 37 is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; a suitable N-protecting 30 group; -(CR 29R ) rOR 3 1 - (CR 29R ) rNR R3; - (CR 29R3 ) rNR "COOR 2 1 ; - (CR 29R ) rNR 2 "COR 3 1 - (CR 2 9 R 30 ) rNR "CONR2 R; -(CR 29R3 )rNR S0 2 R 2 3 ; -(CR 29R )q COOR 2 1 ; - (CR 29R ) qCONR R 1; - (CR 29 R3 ) rSO 2 NR R ; - (CR 29 R 3 0 ) qCOR; 31 - (CR 2 9 R 30 ) qSO 2 R 2 3 ; or - (CR 29 R 3 0 ) 0 R 31 ; 35 WO 2011/015241 PCT/EP2009/060168 482 R is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29R ) qOR 3 ; - (CR 29R ) qNR 28R ; - (CR 29 R 30 ) qNR 2 8 COOR 2 1 ; 29 30 28 3129R3 2 28 31;29 30 2 5 - (CR R ) qNR COR1; - (CR 29 R 3 ) qNR 28 CONR R ; - (CR 2 9 R ) qCOOR ; -(CR 29R )q CONR 2R'; - (CR 29 R3 )qCOR ; or -(CR 29 R 3 0 ) qR 31 ; R 39 ; R 40 ; R 41 ; R 42 ; R 43 ; R 44 ; R 45 ; R 46 ; R 47 ; R 48 ; R 49 and R 50 are as defined in claim 1; 10 the variable heteroatom Z and the connector U are defined as Z being 0; S (=0) ; or S (=O) 2 ; and U being -C (=0)-; -NR 4 -C (=0) -; -C (=0) -C (=0)-; or -C(-OR 2 0 ) 2 -C (=0) -; and - substituents that can be pairwise taken together and 15 form optionally substituted cycloalkyl or heterocycloalkyl moieties; - structural elements that can form one of the groups of formulae H111-H118 (Table 9); - variable heteroatoms Q, T, X and Y; and 20 - indices q-u being defined as in claim 1. 3. Compounds according to claim 2 wherein A is A1(al); 25 A2(al); A3(al); A4(al); A5(al); A6(al); A7(al); A9(al); A10(al); A73(a2); A170(a4); A209(a7); A240(alO); A272(alO); A532(a18); A609(a24); A612(a24) and A614(a24) as shown in Table 13, below; 30 Table 13: Building Blocks of Type A R R R1 R 1 XX -- X X, 0A Al(al) A2(al) A3(al) A4(al) WO 2011/015241 PCT/EP2009/060168 483 R1 1 0 R 1 A5(al) A6(al) A7(al) A9(al) O 1 R 1 NR R1 SS x N. 0 N X 0 A10 (al) A73 (a2) A170 (a4) A209 (a7) R R7 %R1 R 37 N , N - R10N X X x R 38 0 0 0 A240 (alO) A272 (alO) A532 (a18) A609(a24) R1 R1 Ox A612 (a24) A614 (a24) B is B4(b3); B5(b3); B6(b3); B7(b3); B8(b3); B9(b3); B10(b3); B12(b4); B13(b4); B14(b4); B15(b4); B16(b4) or B17(b5) as shown in Table 14, below; 5 Table 14: Building Blocks of Type B R 2 R2 RN3 R R R B4(b3) B5(b3) B6(b3) B7(b3) WO 2011/015241 PCT/EP2009/060168 484 N RRNRNR3 R 2 N R R 3 B8 (b3) B9 (b3) B10 (b3) B12 (b4) R2 ', R 3 R2, R2 N' Ri ' R3 ' ' R3 NZ| R3 R 4 B13 (b4) B14 (b4) B15 (b4) B16 (b4) RN N NN ' R3 B17 (b5) linker C is one of the groups shown in Table 15, below; 5 Table 15: Linkers of type C R 4 R 5 0 R4 R 7 O R4 R 9 R4 R 5 0 R4 R 7 R 3 R 9 I 1 11 I 1 1 111 1 1 1 1 11 I 1 1 1 I --- N-C- C-N-C-- C-N-C--U--- --- N-C- C-N-C--C-Z-C-U-- I I I I I H I RR RL R 10 R 6 R 8 1 0-1 ~-1 0-1 C1 C2 R 4 R 5 R 3 R OR 4 R 9 4 4 R 5 R 4 7 R 1 2 R 9 R4 RI3 R 4 R I 1 11 1 1I I I I 1 11 1 1 --- N-C- C-N-C--C--C-C-U-- --- N-C-C-Z-C-C-N-C-U--- I I I I H I R6 R R13 Rio R6R 1 R8 1 io 0-1 C3 C4 WO 2011/015241 PCT/EP2009/060168 485 R 4 R 5 R 12 R 7 0 R 4 R 9 R 4 R 5 R 3 R 7 R 3 R 9 --- N-C-C---C-C-C-N-C-U--- --- N-C-C-Z-C-C-Z-C-U-- I I I I | | | | R6 R13 R8 Rio R 6 H R 8 H Rio C5 C6 R 4 R 5 R 1 4 0 R 4 R 7 R 1 6 R4 R 5 R 14 R 4 R 16 R 7 I 1 1 | | I I 1 | 1 | | | | 1 --- N-C-C--C-N-C--C---U--- --- N-C- C--C-N--C--C-U-- I I I I I I I I R 6 R 1 5 R 8 R 1 7 R 6 R 1 5 R 1 7 R 8 t_ 0-1 0-1 t C7 C8 R 4 R 14 R 5 0 R4 R 7 R 1 6 R 4 R 14 R 5 0 R 4 Ri 6 R 7 I I | I|| | | |I | |l || i I I --- N-C-C- -C-N-C- -C- -- U--- --- N-C-C-C-N- C- -C-U-- I I I | | 1 | | R 15 R 6 R 8 R 17 R 15 R 6 R 1 7 R 8 0-1 C9 Clo R 4 R 5 R 1 4 R 3 R 16 R 7 R 4 R 5 R 14 R 3 R 7 Ri 6 I 1 | | | 1 1 | 1 | 1 1 --- N-C- C--C-Z- C--C-U --- --- N-C-C-C-Z-C- C- U-- I I | | | | I I I I R 6 R 1 5 H R17 R R 15 H R R 1 7 0-1 t u C1l C12 R 4 R 1 4 R 5 R 3 R 16 R 7 R 4 R 1 4 R 5 R 3 R 7 R 16 I 1 1 | | | 1 | 1 | 1 1 --- N-C-C-C-Z- C--C-U --- --- N-C-C-C-Z-C- C--U-- I I I I | | | | | I R 15 R 6 H R17 R R 15 R 6 H R 8 R 1 7 U U C13 C14 R 4 R 5 R 14 R 1 2 R 16 R 7 R 4 R 5 R 1 4 R 12 R 7 R 16 I I | I | | | | I 1 --- N-C- C--C---C- C--C-U--- --- N-C-C-C---C-C- C--U-- R 6 R 1 5 R 13 R 1 7 R 8 R 6 R 1 5 R 1 3 R 8 R 1 7 0-1 t u C15 C16 WO 2011/015241 PCT/EP2009/060168 486 R 4 R 14 R 5 R 12 R 16 R 7 R 4 R 14 R 5 R 12 R 7 R 16 I I | I | | | | I 1 --- N-C-C-C---C- C--C-U--- --- N-C-C-C---C-C--C-U-- R 15 R 6 R 13 R 1 7 R 8 R 15 R 6 R 13 R 8 R 17 u u C17 C18 R 4 R 5 R 14 R 14 0 R 4 R 7 R 16 R 4 R 5 R 14 R 14 0 R 4 R 16 R 7 R 16 | | | | | | | | 1 | | | | | | | | | 1 --- N-C-C-C--C-N-C- C- U --- N-C-C-C-C-N-C-C--C U-- I | | | I I I I I I I R 6 R 15 R 15 R 8 R 17 R 6 R 15 R 15 R 17 R 8 R 17 t _ 0 1 0-1 C19 C20 R 4 R 5 R 14 R 14 0 R 4 R 16 R 7 R 4 R 14 R 14 R 5 0 R 4 R 7 R 16 I I I I I I | 1 | | | | | | | | | 1 --- N-C-C-C-C-N--C--C-U--- --- N-C-C-C--C-N-C- C- U-- | | | | | | | | | 1 R 6 R 15 R 15 R 17 R 8 R 15 R 15 R 6 R 8 R 17 t- 0-1 C21 C25 R 4 R 14 R 14 R 5 0 R 4 R 16 R 7 R 16 R 4 R 14 R 14 R 5 0 R 4 Ri 6 R 7 I I I | | I | | | | | | | | | 1 | --- N-C-C-C-C-N-C-C- C U--- --- N-C-C-C-C-N--C--C-U-- I I I I I I | | | | | R 15 R 15 R 6 R 17 R 8 R 17 R 15 R 1 5 R 6 R 17 R 8 0-1 u C26 C27 R 4 R 5 R 14 R 14 R 3 R 7 R 16 R 4 R 5 R 14 R 14 R 3 R 16 R 7 R 1 6 1 I 1 | | | | | | | | | | | --- N-C-C-C-C-Z-C-C--U--- --- N-C-C-C-C-Z-C-C- C U-- I I | | | | | | | | | | | R 6 R 15 R 15 H R 8 R 17 R 6 R 15 R 15 H R 17 R 8 R 17 t 0-1 C28 C29 R 4 R 5 R 14 R 14 R 3 R 1 6 R 1 6 R 7 R 4 R 14 R 14 R 5 R 3 R 7 R 16 RI I I I I I I I I I I I I I I --- N-C-C-C-C-Z-C--C-U-- --- N-C-C-C-C-Z-C-C-C-U--- I I I I I I I I I I I 1 1I5 R 5 68 1 R 6 R 15 R 15 H R 17 R 17 R 8 R 15 R 15 R 6 H R 8 R 17 t C30 C34 WO 2011/015241 PCT/EP2009/060168 487 R 4 R 1 4 R 14 R 5 R 3 R 16 R 7 R 16 4 14 14 R 5 3 R 16 R 1 6 7 I I I I I I I IR4 R 4R 4R R3 16 16 7 --- N-C-C-C-C-Z-C-C- C- -U--- _ I I I I I I I I I I I I I I -- N C C C C Z C C C u R 15 R 15 R 6 H R 17 R 8 R 17 I I I I I I I - Ci R 1 5 R 15 R 6 H R 17 R 17 R 8 0-1 C35 C36 R 4 R 5 R 14 R 14 R 12 R 7 R 16 R 4 R 5 R 14 R 14 R 12 R 16 R 7 Ri 6 I | | I I | | I | | |I | | --- N-C-C-C-----C- C- U--- --- N-C-C-C--C=C-C-C -C -U-- | | | I | |I | |I I I I R 6 R 1 5 R 15 R 13 R 8 R 17 R 6 R 15 R 15 R 13 R 17 R 8 R 17 t 0-1 C37 C38 R 4 R 5 R 14 R 14 R 12 R 16 R 16 7 R 4 R 14 R 1 4 R 5 R 1 2 R 7 R 16 R R R R R R RI I I I I I I I I I I I I --- N-C-C--C--CC--C C U-- --- N-C-C-C-C-C-C-C-C-U--- I I I I I I I I I 1 1I5 1 3 8 1 R 6 R 15 R 15 R 13 R 17 R 1 7 R 8 R 15 R 15 6 13 R 8 R 17 t C39 C43 R 4 R 14 R 14 R 5 R 12 R 1 6 R 7 R 16 R 4 R 14 R 14 R 5 R 12 R 16 R 16 7 I I I I I I I R 1 1 5 R2 R6R6R --- N-C-C--C--CC-C--C-C U--- I I I I I I I I I I -- I I I --- N-C-C-C-C-C-C-C-C-U-- R 15 R 15 R 6 R 13 R 17 R 8 R 17 I I I I I I - iR 15 R 15 R 6 R 13 R 17 R 17 R 8 0-1 C44 C45 R 4 R 5 R 14 0 R4 R 7 R4 R 14 R 5 0 R4 R 7 --- N-C--C---C-N-C--U--- --- N--C--C--C-N-C--U-- I I I I I I R 6 R 15 R 15 R 3-5 _ _ 3-5 _ _ 1 C46 C47 R 4 R 5 R 1 4 R 3 Ri 6 R 7 R 4 R 5 R 14 R 12 Ri 6 R 7 --- N-C- C--C-Z- C--C-U--- --- N-C- C--C---C- C--C-U-- R 6 R 1 5 H R 1 7 R 8 R 6 R 1 5 R 13 R 1 7 R 8 3~-5 t 3-5 ~ C48 C49 R 4 R 5 R 14 R 4 0 R 4 R 7 R 16 R 4 R 14 R 5 R 4 0 R 4 R 7 R 16 I I I I I I I I I I I I I I I I I I --- N-C- C--N-C-N-C- C--U--- --- N- C--C-N-C-N-C- C--U-- I I I I I I I I R 6 R 15 R 8 R 17 R 15 R 6 R 8 R 17 1-5 1-5 1-5 1-5 WO 2011/015241 PCT/EP2009/060168 488 C50 C51 R 4 R 14 R 5 R4 0 R 4 R 16 R 7 R 4 R 5 R 14 R 4 0 R 4 R 1 6 R 7 II I | | | | | | | | | | --- N--C--CC-N- -- C-- C-U--- --- N-C--C--N-C-N--C-- C-U-- I I |I |I R 15 R 6 R 1 7 R 8 R 6 R 1 5 R 17 R 8 1-5 1-5 1-5 1-5 C52 C53 R 4 R 5 R 1 4 0 R 4 R 7 R 1 6 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N-C--C--C-N-C--C--C-N-C-U-- I I I I I R 6 R 15 R 8 R 17 Rl0 t u C54 R 4 R 14 R 5 0 R 4 R 7 Ri 6 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N--C--C-C-N-C--C--C-N-C-U-- I I I I I R 1 5 R 6 R 8 R 1 7 Rl0 u u C55 R 4 R 1 4 R 5 0 R 4 R 16 R 7 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N--C--C-C-N--C--C-C-N-C-U-- I I I I I R 15 R 6 R 1 7 R 8 Rl0 u u C56 R 4 R 5 R 14 0 R 4 R 16 R 7 0 R 4 R 9 I I 1 | | | 1 1 | | | 1 --- N-C--C--C-N--C--C-C-N-C-U-- I I I I I R 6 R 15 R 1 7 R 8 Rl0 t u C57 R 4 R 5 R 14 R 3 R 7 R 16 0 R4 R 9 I I I I I 1 | | | 1 --- N-C--C--C-Z-C- C--C-N-C-U-- R 6 R 1 5 H R 8 R 17 Rl0 t u C58 WO 2011/015241 PCT/EP2009/060168 489 R 4 R 14 R 5 R 3 R 7 R 6 0 R4 R 9 I I I I I I I I I I --- N- C--C-C-Z-C--C--C-N-C-U-- R 1 5 R 6 H R 8 R 1 7 Rl0 u u C59 R 4 R 14 R 5 R 3 R 16 R 7 0 R4 R 9 I I I I I I I I I I --- N--C--C-C-Z--C--C-C-N-C-U-- R 15 R 6 H R 1 7 R 8 u u C60 R 4 R 5 R 14 R 3 R 16 R 7 0 R4 R 9 I I I I I 1 | | | 1 --- N-C--C--C-Z--C--C-C-N-C-U-- I I | | 1 I R 6 R 15 H R 1 7 R 8 R t u C61 R 4 R 5 R 14 0 R 4 R 7 R 16 R 3 R 9 I I 1 | | | 1 | 1 1 --- N-C--C--C-N-C--C--C-Z-C-U-- I I 1 I | | R 6 R 15 R 8 R 1 7 H t u C62 R 4 R 14 R 5 0 R4 R 7 R 16 R 3 R 9 I I 1 | | | 1 | 1 1 --- N--C--C-C-N-C--C--C-Z-C-U-- R 15 R 6 R 8 R 1 7 H u u C63 R 4 R 14 R 5 0 R 4 R 16 R 7 R 3 R 9 I I 1 | | | 1 1 1 1 --- N--C--C-C-N--C--C-C-Z-C-U-- R 15 R 6 R 1 7 R 8 H u u C64 WO 2011/015241 PCT/EP2009/060168 490 R 4 R 5 R 14 0 R 4 R 16 R 7 R 3 R 9 I I I || | | | | | --- N-C--C--C-N--C--C-C-Z-C-U-- I I I 1 | | R 6 R 15 R 1 7 R 8 H t u C65 R 4 R 5 R 14 R 3 R 7 R 16 R 3 R 9 I I I I I I I I --- N-C--C--C-Z-C--C--C-Z-C-U-- I I | 1 I | 1 R 6 R 15 H R 8 R 17 H t u C66 R 4 R 14 R 5 R 3 R 7 R 16 R 3 R 9 I I I I I I I I --- N- C--C-C-Z-C--C--C-Z-C-U-- | 1 6 1 8 |7 1 R 15 R 6 H R 8 R 17 H Rl0 u u C67 R 4 R 14 R 5 R 3 R 16 R 7 R 3 R 9 I I I I I I I I --- N- C--C-C-Z--C--C-C-Z-C-U-- R 15 R 6 H R 17 R 8 H Rl0 u u C68 R 4 R 5 R 14 R 3 R 16 R 7 R 3 R 9 I I I I I I I I --- N-C--C--C-Z--C--C-C-Z-C-U-- I I | I 1 | | R 6 R 1 5 H R 1 7 R 8 H t u C69 R 4 R 5 R 14 0 R4 R 7 R 16 R 1 2 R 9 I I I || | | | I --- N-C- -C--C-N-C -- C--CC-C-U-- R 6 R 1 5 R 8 R 17 R 1 3 R 1 0 t u C70 WO 2011/015241 PCT/EP2009/060168 491 R 4 R 14 R 5 0 R4 R 7 R 16 R 12 R 9 --- N--C--C-C-N-C--C--C=C-C-U-- I I I | I R 15 R 6 R 8 R 1 7 R 13 R 10 u u C71 R 4 R 14 R 5 0 R 4 R 16 R 7 R 12 R 9 I I I I I I 1 1 4 --- N--C--C-C-N--C--C-C=C-C-U-- I I | | I R 15 R 6 R 1 7 R 8 R 13 R 10 u u C72 R 4 R 5 R 14 0 R 4 R 16 R 7 R 12 R 9 I I I I I I 1 1 4 --- N-C--C--C-N--C--C-C=C-C-U-- R 6 R 15 R 1 7 R 8 R 13 R 10 t u C73 R 4 R 5 R 14 R 1 2 R 7 R 16 0 R 4 R 9 --- N-C--C--C=C-C--C--C-N-C-U-- 1 |I I | | R 6 R 15 R 1 3 R 8 R 17 Rl0 t u C74 R 4 R 14 R 5 R 12 R 7 R 6 0 R4 R 9 I 1 1 4 1 1 | | | 1 --- N--C--C-C=C-C- -C--C-N-C-U-- I I I | |I R 1 5 R 6 R 13 R 8 R 1 7 Rl0 u u C75 R 4 R 14 R 5 R 1 2 Ri 6 R 7 0 R4 R 9 I 1 1 4 1 1 | | | 1 --- N--C--C-C=C- C--C-C-N-C-U-- I I I I | R 15 R 6 R 13 R 17 R 8 Rl0 u u C76 WO 2011/015241 PCT/EP2009/060168 492 R 4 R 5 R 14 R 1 2 R 16 R 7 0 R4 R 9 I I I I | || | | --- N-C--C--C-C--C--C-C-N-C-U-- R 6 R 15 R 13 R 17 R 8 Rl0 t u C77 R 4 R 5 R 1 4 R 1 2 R 7 R 16 R 3 R 9 | | |I I I | | --- N-C--C--C=C-C--C--C-Z-C-U-- 1 |I I | | | R 6 R 15 R 1 3 R 8 R 1 7 H t u C78 R 4 R 14 R 5 R 12 R 7 Ri 6 R 3 R 9 I I |I I I | | --- N--C--C-C-C-C--C--C-Z-C-U-- I I I | | | R 15 R 6 R 13 R 8 R 1 7 H u u C79 R 4 R 1 4 R 5 R 1 2 R 1 6 R 7 R 3 R 9 I I |I I I I I --- N--C--C-C-C- C--C-C-Z-C-U-- I I I I | | R 15 R 6 R 1 3 R 1 7 R 8 H u u C80 R 4 R 5 R 14 R 1 2 R 1 6 R 7 R 3 R 9 I I I I | | 1 --- N-C--C--C=C--C--C-C-Z-C-U-- R 6 R 15 R 1 3 R 17 R 8 H t u C81 R 4 R 5 R 14 R 3 R 7 R 1 6 R 1 2 R 9 I I I | | |I I --- N-C--C--C-Z-C--C--C=C-C-U-- R 6 R 15 H R 8 R 17 R 1 3 R 10 t u C86 WO 2011/015241 PCT/EP2009/060168 493 R 4 R 14 R 5 R 3 R 7 R 16 R 12 R 9 I I | | | | I --- N--C--C-C-Z-C--C--C=C-C-U-- R 1 5 R 6 H R 8 R 1 7 R 13 R 10 u u C87 R 4 R 1 4 R 5 R 3 R 16 R 7 R 12 R 9 I I | | | | I --- N--C--C-C-Z--C--C-C=C-C-U-- R 15 R 6 H R 17 R 8 R 13 R 10 u u C88 R 4 R 5 R 14 R 3 R 16 R 7 R 12 R 9 I I I | | | I --- N-C--C--C-Z--C--C-C=C-C-U-- I | 1 18 > R 6 R 15 H R 17 R 8 R Rl t u C89 R 4 R 5 R 14 R 4 0 R 7 R 16 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N-C--C--N-C-C--C---C-N-C--U-- I I I I I R 6 R 1 5 R 8 R 1 7 Rl0 1-5 t _ _ 1 C90 R 4 R 14 R 5 R 4 0 R 7 R 16 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N--C--C-N-C-C--C---C-N-C--U-- I I I I I R 15 R 6 R 8 R 1 7 Rl0 1-5 t_ _ 01 C91 R 4 R 14 R 5 R 4 o R 16 R 7 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N--C--C-N-C- C--C--C-N-C--U-- I I I I I R 15 R 6 R 1 7 R 8 Rl0 1-5 t _ 1 C92 WO 2011/015241 PCT/EP2009/060168 494 R 4 R 5 R 1 4 R 4 0 R 16 R 7 0 R 4 R 9 I I I | | | | 1 | | | 1 --- N-C--C--N-C--C--C--C-N-C--U-- I I I I I R 6 R 1 5 R 17 R 8 R10 1-5 t __ 1 C93
4. Compounds according to claim 3 wherein the building blocks of type A are A1(al); A2(al); A3(al); A4(al); A5(al); A6(al); A7(al); A9(al); A10(al); A73(a2); A170(a4); 5 A209(a7); A240(alO); A272(alO); A532(a18); A614(a24) as shown in Table 16, below; Table 16: Building Blocks of Type A R 1 0' 0" 0 A1(al) A2(al) A3(al) A4(al) R1 0 R 1 0: ax 0 x Q& A5(al) A6(al) A7(al) A9(al) R 1 R1 0 0 ( 0: N S 0 A1O(al) A73(a2) A170(a4) A209(a7) WO 2011/015241 PCT/EP2009/060168 495 R 37 R1 R1R N R1 ~ 0 N 0 R 38 0,I A272(alO) A532 (a18) A614 (a24) the building blocks of type B are B7, B8, B9 and B-17 as shown in Table 17, below; 5 Table 17: Building Blocks of Type B R 20-0 R 20-0 R20-0 R 20.0 ' R3 ' R3 ' R3 ' R3 B7-1 B7-2 B7-3 B7-4 0 'R20 0 'R20 O'R2o ,O'R2o R 3 R 3 R 3 R 3 B8-1 B8-2 B8-3 B8-4 R 27 R 27 R 27 R 27 RNN R N R N ' R3 ' R3 ' R3 ' R3 B9-1 B9-2 B9-3 B9-4 R11 R11 N N R 3 R 3 B17-1 B17-2 the linkers C are those listed in Table 18, below; WO 2011/015241 PCT/EP2009/060168 496 Table 18: Embodiments of Linker C R 4 R 5 0 R4 R 7 0 R4 R 9 R4 R 5 0 R4 R 7 R 3 R 9 I 1 1 1 1 1 1 1 1 1 1 1 1 --- N-C-C-N-C---C-N-C--U--- --- N-C- C-N-C--C-Z-C-U-- I I I I I H I R 4 RRR1R R 1 2 R1 9 0-1 6-1 0-1 C1 C2 R4 RR3 R7 O 4 RR 4 R5 0R4 R7 R12 R9 R5 3 R 7 0 R 4 R 9 I 1 1 1 I I I 1 11 1 1 --- N-C- C-N-C--Cr-C-U-- --- N-C-C-Z-C-C-N-C-U--- I I I I H I R6 R R 13 R 10 R 6 R 8 Rio 0 0-1 C3 C4 R 4 R 5 R 12 R 7 0 R 4 R 9 R 4 R 5 R 3 R 7 R 3 R 9 | | I ||I I | | | | | | | --- N-C-C---C-C-C-N-C-U--- --- N-C-C-Z-C-C-Z-C-U-- I I I | | | | | R6 R13 R8 Rio R 6 H R 8 H Rio C5 C6 R 4 R 5 R 1 4 0 R 4 R 7 R 1 6 R4 R 5 R 1 4 0 R 4 R 1 6 R 7 1 1 1 | | 1 1 | 1 | 1 | | 1 | 1 --- N-C-C--C-N-C--C---U--- --- N-C- C--C-N- C--C-U-- RR R 1 5 R 8 R 1 7 R 6 R 15 R 1 7 R 8 t 0-1 0-1 t C7 C8 R 4 R 1 4 R 5 0 R4 R 7 R 1 6 R 4 R 14 R 5 0 R 4 R 1 6 R 7 | | | I|| | | |I | |l || i I I --- N-C-C- -C-N-C- C- -- U--- --- N-C-C-C-N- C- -C-U-- I I I | | 1 | | R 1 5 R 6 R 8 R 17 R 15 R 6 R 1 7 R 8 0-1 C9 C10 R 4 R 5 R 1 4 R 3 R 16 R 7 R 4 R 5 R 14 R 3 R 7 R 1 6 I 1 | | | 1 1 | 1 | 1 1 --- N-C- C--C-Z- C--C-U --- --- N-C-C-C-Z-C- C--U-- I 1 1 | 8 6 1 I I I R 6 R 1 5 H R R R R 15 H R 8 R 1 7 0-1 t u C1l C12 WO 2011/015241 PCT/EP2009/060168 497 R 4 R 14 R 5 R 3 R 1 6 R 7 R 4 R 1 4 R 5 R 3 R 7 R 1 6 I 1 1 | | | 1 | 1 | 1 1 --- N-C-C-C-Z- C--C-U--- --- N-C-C-C-Z-C-C--U-- R 15 R H R1R 15 R H R R 1 7 u u C13 C14 R 4 R 5 R 1 4 R 1 2 R 16 R 7 R 4 R 5 R 1 4 R 12 R 7 R 16 I I | I | | | | I 1 --- N-C- C--C---C--C--C-U--- --- N-C-C-C---CC--U-- R 6 R 1 5 R 13 R 1 7 R 8 R 6 R 1 5 R 1 3 R 8 R 1 7 0-1 t u C15 C16 R 4 R 1 4 R 5 R 1 2 R 16 R 7 R 4 R 14 R 5 R 12 R 7 R 16 I I | I | | | | I 1 --- N-C-C-C---C- C--C-U--- --- N-C-C-C---CC--U-- R 1 5 R 6 R 1 3 R 1 7 R 8 R 15 R 6 R 1 3 R 8 R 1 7 u u C17 C18 R 4 R 5 R 14 R 14 0 R 4 R 7 R 16 R 4 R 5 R 14 R 14 0 R 4 R 16 R 7 R 16 | | | | | | | | 1 | | | | | | | | | 1 --- N-C-C-C--C-N-C- C- U --- N-C-C-C-C-N-C-C- C- U-- I | | | I | | | | | | R 6 R 15 R 15 R 8 R 17 R 6 R 15 R 15 R 17 R 8 R 17 t _ 0 1 0-1 C19 C20 R 4 R 5 R 14 R 14 0 R 4 R 16 R 7 R 4 R 14 R 14 R 5 0 R 4 R 7 R 16 I I I I I I | 1 | | | | | | | | | 1 --- N-C-C-C-C-N--C--C-U--- --- N-C-C-C--C-N-C- C- U-- | | | | | | | | | 1 R 6 R 15 R 15 R 17 R 8 R 1 5 R 1 5 R 6 R 8 R 1 7 t 0-1 C21 C25 R 4 R 14 R 14 R 5 0 R 4 R 16 R 7 R 16 R 4 R 14 R 14 R 5 0 R 4 Ri 6 R 7 I I I | | I | | | | | | | | | 1 | --- N-C-C-C-C-N-C-C- C U--- --- N-C-C-C-C-N- C--C-U-- I I I I I I | | | | | R 15 R 15 R 6 R 17 R 8 R 1 7 R 15 R 1 5 R 6 R 17 R 8 0-1 u C26 C27 WO 2011/015241 PCT/EP2009/060168 498 R 4 R 5 R 14 R 14 R 3 R 7 R 16 R 4 R 5 R 14 R 14 R 3 R 16 R 7 R 16 1 I 1 | | | | | | | | | | | --- N-C-C-C-C-Z-C--C--U--- --- N-C-C-C-C-Z-C-C--C U-- I I | | | | | | | | | I I R 6 R 15 R 15 H R 8 R 1 7 R 6 R 15 R 15 H R 17 R 8 R 17 t 0-1 C28 C29 R 4 R 5 R 14 R 14 R 3 R 1 6 R 1 6 7 R 4 R 14 R 14 R 5 R 3 R 7 R 16 R R R R RI I I I I I I I I I I I I I I --- N-C--C--C-C-Z-C--C-U-- --- IN-C-C-C-C-Z-C-C-C-U--- NI I I I I R 6 R 15 R 15 H R 17 R 17 R 8 R 15 R 15 R 6 H R 8 R 17 t C30 C34 R 4 R 14 R 14 R 5 R 3 R 16 R 7 R 16 R 4 R 14 R 14 R 5 R 3 R 16 R 16 R 7 1I I I R R R R RI --- N-C-C--C--C-Z- C--C C U---I I I I I I I I I I I I I I I --- N-C-C-C-C-Z-C-C-C-U-- R 15 R 15 R 6 H R 17 R 8 R 17 I I I I I I I - iR 1 5 R 15 R 6 H R 17 R 17 R 8 0-1 C35 C36 R 4 R 5 R 14 R 14 R 12 R 7 R 16 R 4 R 5 R 14 R 14 R 12 R 16 R 7 R 16 I | | I I | | I | | |I | | --- N-C-C-C--C-C--C C- C- U--- --- N-C-C-C-C=C-C-C- C -U-- | | | I I |I | |I I I | R 6 R 1 5 R 15 R 13 R 8 R 17 R 6 R 15 R 15 R 13 R 17 R 8 R 17 t 0-1 C37 C38 R 4 R 5 R 14 R 14 R 12 R 16 R 16 7 R 4 R 14 R 1 4 R 5 R 1 2 R 7 R 16 R R R R RI I I I I I I I I I I I I --- N-C-C--C--CC--C C U-- --- N-C-C-C-C-C--C-C-C-U--- I I I I I R 6 R 15 R 15 R 13 R 17 R 1 7 R 8 R 15 R 1 5 R 6 R 13 R 8 R 17 t C39 C43 R 4 R 14 R 14 R 5 R 12 R 16 R 7 R 1 6 R 4 R 14 R 1 4 R 5 R 1 2 R 16 R 1 6 R 7 --- N-C-C--C--CC -C--C C U--- I I I I I I I -- C --- C- -U --- N-C-C-C-C-C--C-C-C-U-- R 15 R 15 R 6 R 13 R 17 R 8 R 1 7 1 15 1 13 17 117 1 8 - iR 15 R 15 R 6 R 1 R 1 R 1 R 8 0-1 C44 C45 R 4 R 5 R 14 0 R4 R 7 R4 R 14 R 5 0 R4 R 7 --- N-C--C---C-N-C--U--- --- N--C--C--C-N-C--U-- I I I I I I R 6 R 15 R 1 5 R 3-5 _ 3-5 _ WO 2011/015241 PCT/EP2009/060168 499 C46 C47 R 4 R 5 R 1 4 R 3 R 16 R 7 R 4 R 5 R 1 4 R 1 2 R 16 R 7 I |I | | | |I --- N-C- C--C-Z--C--C-U --- --- N-C- C--C---C--C--C-U-- I | |I I R 6 R 15 H R 1 7 R 8 R 6 R 1 5 R 13 R 1 7 R 8 3-5 t 3-5 t C48 C49 R 4 R 5 R 14 0 R 4 R 7 R 16 0 R 4 R 9 I I I I I I I I I I I I --- N-C--C--C-N-C--C--C-N-C-U-- I I I I I R 6 R 15 R 8 R 17 Rl0 t u C54 R 4 R 14 R 5 0 R 4 R 7 R 16 0 R 4 R 9 I I I I I I I I I I I I --- N--C--C-C-N-C--C--C-N-C-U-- I I I I I R 1 5 R 6 R 8 R 1 7 Rl0 u u C55 R 4 R 1 4 R 5 0 R 4 R 1 6 R 7 0 R 4 R 9 I I I I I I I I I I I I --- N--C--C-C-N- -C--C-C-N-C-U-- I I I I I R 15 R 6 R 1 7 R 8 Rl0 u u C56 R 4 R 5 R 14 0 R 4 R 1 6 R 7 0 R 4 R 9 I I I I I I I I I I I I --- N-C- C--C-N--C--C-C-N-C-U-- I I I I I R 6 R 1 5 R 1 7 R 8 Rl0 t u C57 R 4 R 5 R 14 R 3 R 7 R 16 0 R4 R 9 I I I I I 1 | | | 1 --- N-C--C--C-Z-C- C--C-N-C-U-- R 6 R 1 5 H R 8 R 17 Rl0 t u C58 WO 2011/015241 PCT/EP2009/060168 500 R 4 R 14 R 5 R 3 R 7 R 6 0 R4 R 9 I I I I I I I I I I --- N- C--C-C-Z-C--C--C-N-C-U-- | 1 | 1 I | R 1 5 R 6 H R 8 R 1 7 Rl0 u u C59 R 4 R 14 R 5 R 3 R 16 R 7 0 R4 R 9 I I I I I I I I I I --- N--C--C-C-Z--C--C-C-N-C-U-- R 1 5 R 6 H R 1 7 R 8 u u C60 R 4 R 5 R 1 4 R 3 R 16 R 7 0 R4 R 9 I I I I I 1 | | | 1 --- N-C--C--C-Z--C--C-C-N-C-U-- I I | | 1 I R 6 R 1 5 H R 1 7 R 8 R t u C61 R 4 R 5 R 14 0 R 4 R 7 R 16 R 3 R 9 I I 1 | | | 1 | 1 1 --- N-C--C--C-N-C--C--C-Z-C-U-- I I 1 I | | R 6 R 15 R 8 R 1 7 H t u C62 R 4 R 14 R 5 0 R4 R 7 R 16 R 3 R 9 I I 1 | | | 1 | 1 1 --- N--C--C-C-N-C--C--C-Z-C-U-- R 1 5 R 6 R 8 R 17 H u u C63 R 4 R 14 R 5 0 R 4 R 16 R 7 R 3 R 9 I I 1 | | | 1 1 1 1 --- N--C--C-C-N--C--C-C-Z-C-U-- R 1 5 R 6 R 17 R 8 H u u C64 WO 2011/015241 PCT/EP2009/060168 501 R 4 R 5 R 14 0 R 4 R 16 R 7 R 3 R 9 I I I || | | | | | --- N-C--C--C-N--C--C-C-Z-C-U-- | | | | | | R 6 R 1 5 R 17 R 8 H t u C65 R 4 R 5 R 14 0 R4 R 7 R 16 R 12 R 9 I I I || | | | I --- N-C--C--C-N-C--C--C=C-C-U-- R 6 R 15 R 8 R 17 R 13 R 10 t u C70 R 4 R 14 R 5 0 R4 R 7 R 16 R 1 2 R 9 | | | || | | |I I --- N- -C--C-C-N-C--C--C=C-C-U-- I I I | I R 1 5 R 6 R 8 R 17 R 1 3 R 10 u u C71 R 4 R 14 R O R 4 R 16 R 7 R 1 2 R 9 I I | || | | |I I --- N--C--C-C-N--C--C-C=C-C-U-- I I | | I R 15 R 6 R 1 7 R 8 R 1 3 R 10 u u C72 R 4 R 5 R 14 0 R4 R 16 R 7 R 1 2 R 9 I I | || | | |I I --- N-C- C--C-N- -C--C-C=C-C-U-- R 6 R 1 5 R 1 7 R 8 R 13 R 10 t u C73 R 4 R 5 R 14 R 1 2 R 7 R 16 0 R 4 R 9 --- N-C- -C--C=C-C- C--C-N-C-U-- 1 |I I | | R 6 R 1 5 R 1 3 R 8 R 1 7 Rl0 t u C74 WO 2011/015241 PCT/EP2009/060168 502 R 4 R 14 R 5 R 12 R 7 R 6 0 R4 R 9 I I | I | || | | --- N--C--C-C=C-C--C--C-N-C-U-- I I I | |I R 1 5 R 6 R 1 3 R 8 R 1 7 Rl0 u u C75 R 4 R 14 R 5 R 1 2 Ri 6 R 7 0 R4 R 9 I 1 1 4 1 1 | | | 1 --- N--C--C-C=C- C--C-C-N-C-U-- I I I I | R 15 R 6 R 13 R 17 R 8 Rl0 u u C76 R 4 R 5 R 14 R 1 2 R 16 R 7 0 R4 R 9 I I 1 4 1 1 | | | 1 --- N-C--C--C=C--C--C-C-N-C-U-- R 6 R 15 R 13 R 17 R 8 Rl0 t u C77 R 4 R 5 R 14 R 4 0 R 7 R 16 0 R 4 R 9 I I I I I I I I I I I I --- N-C--C--N-C-C--C---C-N-C--U-- I I I I I R 6 R 1 5 R 8 R 1 7 Rl0 1-5 t 01 C90 R 4 R 14 R 5 R 4 0 R 7 R 1 6 0 R 4 R 9 I I I I I I I I I I I I --- N--C--C-N-C-C--C---C-N-C--U-- I I I I I R 15 R 6 R 8 R 1 7 Rl0 1-5 t_ _ 01 C91 R 4 R 14 R 5 R 4 o R 16 R 7 0 R 4 R 9 I I I | | | I 1 | | | 1 --- N--C--C-N-C- C--C--C-N-C--U-- I I I I I R 15 R 6 R 1 7 R 8 Rl0 1-5 t _ 1 C92 WO 2011/015241 PCT/EP2009/060168 503 R 4 R 5 R 1 4 R 4 0 R 16 R 7 0 R 4 R 9 I I I 1 1 1 1 1 1 1 1 1 --- N-C--C--N-C--C--C--C-N-C--U-- I I I I I R 6 R 1 5 R 17 R 8 R10 1-5 t 0-1 C93 5 R' is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; lower alkyl; lower alkenyl; lower alkynyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR1 8 R1 9 ) qOR 20 ; - (CR 8 R'9) qNR 4 R"; - (CR 8 R' 9 ) qNR 4 COR 22 ; 10 - (CR "R19) qNR4CONR R"; - (CR "R 9) qNR 4 SO 2 R 23 ; - (CR 8 R 9 ) qNR 4 SO 2 NR 4 R"; - (CR "R19) qCOOR 21 ; - (CR 8 R1 9 ) qCONR 4 R"; - (CR "R19) qSO 2 NR 4 R"; - (CR R 19) qCOR 2 ; - (CR' 8 R1 9 ) qSO 2 R 23 ; - (CR 8 R1 9 ) qR 24 ; - (CR 8 R1 9 ) qR 25 ; or -(CR R18 19) R26; 15 R2 is H; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR R 19) qOR 20 ; - (CR "R 9) qNR 4 R"; - (CR 8 R 9 ) qNR 4 COR 22 ; - (CR "R19) qNR 4CONR4 R"; - (CR "R 9) qNR 4 SO 2 R 23 ; - (CR 8 R 9 ) qNR 4 SO 2 NR 4 R"; 20 - (CR "R19) qCOOR 21 ; - (CR 8 R1 9 ) qCONR 4 R"; - (CR "R19) qSO 2 NR 4 R"; - (CR1 8 R1 9 ) qCOR 22 ; - (CR' 8 R1 9 ) qSO 2 R 23 ; - (CR 8 R1 9 ) qR 24 ; - (CR 8 R1 9 ) qR 25 ; or - (CR 8 R1 9 ) qR 2 . R 3 is as defined in claim 1; 25 R 4 is H; lower alkyl; lower alkenyl; or a suitable N protecting group; R , R 7 and R 9 are independently defined as: H; CF 3 ; 30 lower alkyl; lower alkenyl; lower cycloalkyl; lower WO 2011/015241 PCT/EP2009/060168 504 heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR R 19) OR 2 0 ; - (CR"R 9) NR 4 R"; - (CR"R' 9 ) sNR 4 COR 2 2 ; - (CR"R19) sNR 4CONR4 R"; - (CR"R 9) sNR 4 SO 2 R; 2 3 - (CR'"R1 9 ) qCOOR; 2 1 5 - (CR'"R1 9 ) qCONR 4 R"; - (CR'"R1 9 ) qSO 2 NR 4 R1; - (CR'"R1 9 ) COR 2 2 ; - (CR R19) qSO 2 R 23 ; - (CR1 8 R1 9 ) qR 24; - (CR1 8 R1 9 ) qR 25 ; or - (CR1 8 R1 9 ) qR 2 6 ; R , R 8 and R 10 are independently defined as: H; CF 3 ; or CH 3 ; 10 R" is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; a suitable protecting group; - (CR R19) rOR 20 ; - (CR R 9) rNR 4 R; 2 7 - (CR'"R' 9 ) rNR 4 CONR 4 R; 2 7 15 - (CR'"R' 9 ) rNR 4 SO 2 R; 2 3 - (CR'"R 19 ) qCOOR 2 1 ; - (CR"R19) qCONR4 R ; - (CR1 8 R 9 ) qCOR 2 ; - (CR1 8 R1 9 ) qR 24 ; - (CR1 8 R' 9 ) R 2 5 ; or - (CR1 8 R1 9 ) qR 2 6 ; R and R1 3 are independently defined as H; or lower 20 alkyl; R 14 and R1 6 are independently defined as: H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower 25 heteroarylalkyl; -(CR R )sOR 20; - (CR"R9) sNR4R"; - (CR R9) sNR4COR 2 2 ; - (CR'"R1 9 ) qCOOR 2 1 ; or - (CR"R19) gCONR 4 R1; R 15 and R1 7 are independently defined as: H; CF 3 ; or CH 3 ; 30 R" is H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; -(CR 29R ) sOR 3 1 ; - (CR 29R ) sNR R3; 35 -(CR 2 9 R 30 ) sNR COR 3 1 ; - (CR 2 9 R 30 ) sNR 2 CONR 2 "R 3 1 ; -(CR 2 9 R 30 ) sNR 2 8 SO 2 R; 2 3 - (CR 29R ) qCOOR 21 ; - (CR 2 9 R 30 ) qCONR 2 "R 31 ; - (CR R ) qSO 2 NR R3; WO 2011/015241 PCT/EP2009/060168 505 29 035 - (CR 29R ) qCOR 3 1 ; - (CR 29 R 30 ) qSO 2 R 2 3 ; - (CR 29 R 3 0 ) qR 24 ; - (CR 29R ) qR 25 ; or - (CR 2 9 R 3 0 ) qR 2 6 ; R' 9 is H; CF 3 ; or CH 3 ; 5 R is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29R ) rOR 3 1 ; - (CR 29R ) rNR R ; - (CR 29 R 30 ) rNR 2 "COR; 3 1 10 - (CR 29R3 ) rNR "CONR "R ; - (CR 29 R 3 0 ) rNR S0 2 R 23 ; - (CR R ) qCOOR 21 ; - (CR R ) qCONR R 1; - (CR 29 R3 ) qSO 2 NR R ; - (CR 29 R 30 ) qCOR 3 1 ; - (CR R ) qSO 2 R 23 ; - (CR 29 R 3 0 ) qR 24; - (CR 2 9 R 3 0 ) qR 25 ; or - (CR 2 9 R 3 0 ) qR 2 6 ; R and R 23 are as defined in claim 1; 15 R is lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29R ) sOR 3 1 ; - (CR 29R ) sNR R ; - (CR 29 R 30 ) SNR 2 "COR3 20 - (CR 29R ) N 2CONR 2 "R 3 1 ; - (CR 29R ) NR 2 SO 2 R 2 3 ; - (CR 2 9R ) sCOOR 2 1 ; -(CR 2 9 R 30 ) SCONR R 3 1 ; -(CR 29R ) SO 2 NR R ; -(CR 2 9 R 30 ) tCOR; 3 1 -(CR 29R ) SO 2 R 23 ; -(CR 29 R 3 0 ) tR24; -(CR 29R ) tR 25 ; or (CR29R30) tR2; 25 R 24, R, 2 5 R, 2 6 R 27 and R 2 " are as defined in claim 1; R29 is H; F; CF 3 ; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; 30 -(CR3 R) OR 3 1 ; - (CR3 R) SNR R3; 32 33 28 3; 3 33 2 28 31;3 332 - (CRR ) NR "COR1; - (CR 3 R 3 ) SNR 28 CONR R ; - (CR 3 R 3 ) qCOOR 2 ; - (CR 32 3 3 ) qCONR R 3 1 ; - (CR R ) qCOR 31 ; or - (CR 3 2 R 3 3 ) qR; 3 1 R and R 3 3 are H; CF 3 ; or CH 3 ; 35 WO 2011/015241 PCT/EP2009/060168 506 R 3 and R 32 are as defined in claim 1; R 34 and R 35 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; lower alkyl; lower alkenyl; lower alkynyl; lower 5 cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29 R 30 ) qOR 3 ; - (CR 29 R 30 ) qNR 28 R; 31 - (CR R ) qNR 2COR 1; - (CR 29 R 30 ) qNR 28 CONR 2R ; - (CR 29 R 30 ) qNR 28 SO 2 R; 2 3 -(CR 29R ) qCOOR 21 ; 10 - (CR R ) qCONR 2R 1; - (CR 29 R3 ) qSO 2 NR 2R ; - (CR 29 R 30 ) qCOR 31 ; - (CR R ) qSO 2 R 23 ; or - (CR 29 R 30 ) qR; 31 15 R 3 6 is as defined in claim 1; R 37 is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; 20 lower heteroarylalkyl; a suitable N-protecting group; -(CR 29R3 )rOR 3 1 ; - (CR 29R ) rNR 28R ; - (CR 29R3 ) rNR 2COOR 2 1 ; - (CR 29R ) rNR 28 COR; 3 1 - (CR 2 9 R 30 ) rNR 2CONR 28R ; - (CR 29R ) qCOOR 21 ; - (CR 2 9 R 30 ) qCONR 28 R 31 ; - (CR 29R ) qCOR; 31 or - (CR 29 R 30 ) qR; 3 1 25 R 3 1 is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower heterocycloalkyl; aryl; heteroaryl; lower arylalkyl; lower heteroarylalkyl; - (CR 29R ) qOR 3 1 ; - (CR 29R ) qNR 28R ; - (CR 29 R 30 ) qNR 28 COR 3 1 ; 30 -(CR 29R ) NR 28CONR 28R; - (CR R ) qCOOR 21 ; - (CR 2 9 R 30 ) qCONR 28 R 31 ; - (CR 29R ) qCOR; 31 or - (CR 29 R 30 ) qR 31 ; R 39; R 4 0 ; R 41 ; R 42; R 43 ; R 4 4 ; R 45 ; R 4 6 ; R 47 ; R 4 8 ; R 4 9 and R 5 0 35 are as defined in claim 1; WO 2011/015241 PCT/EP2009/060168 507 the variable heteroatom Z and the connector U are defined as: Z: 0; or S(=0)2. U: -C(=0)-; -NR4-C(=O)-; or -C(=0)-C(=0)-; and 5 - substituents that can be pairwise taken together and form optionally substituted cycloalkyl or heterocycloalkyl moieties; - structural elements that can form one of the groups of 10 formulae H111-H118 as shown in Table 9; and - variable heteroatoms Q, T, X and Y; - indices q-u; are as defined in claim 1. 15 5. Compounds according to claim 1 wherein readily accessible substances that define possible subunits of the linker C are those listed in Table 19, below; Code Chemical Name Ala L-Alanine DAla D-Alanine Arg L-Arginine DArg D-Arginine Asn L-Asparagine DAsn D-Asparagine Asp L-Aspartic acid DAsp D-Aspartic acid Cys L-Cysteine DCys D-Cysteine Glu L-Glutamic acid DGlu D-Glutamic acid Gln L-Glutamine DGln D-Glutamine Gly Glycine His L-Histidine DHis D-Histidine Ile L-Isoleucine WO 2011/015241 PCT/EP2009/060168 508 Code Chemical Name DIle D-Isoleucine Leu L-Leucine DLeu D-Leucine Lys L-Lysine DLys D-Lysine Met L-Methionine DMet D-Methionine Phe L-Phenylalanine DPhe D-Phenylalanine Pro L-Proline DPro D-Proline Ser L-Serine DSer D-Serine Thr L-Threonine DThr D-Threonine Trp L-Tryptophan DTrp D-Tryptophan Tyr L-Tyrosine DTyr D-Tyrosine Val L-Valine DVal D-Valine Apa 3-Amino-propanoic acid H-P 3 -HAla-OH (3S)-3-Amino-butyric acid H-P 3 -HVal-OH (3R)-3-Amino-4-methyl-valeric acid H- 3-HIle-OH (3R, 4S)-3-Amino-4-methyl-hexanoic acid H- 3 -HLeu-OH (3S)-3-Amino-5-methyl-hexanoic acid H- 3 -HMet-OH (3S)-3-Amino-5-methylthio pentanoic acid (3S)-3-Amino-4-(4'-hydroxyphenyl)-butyric H- 3 -HTyr-OH acid H . (3S)-3-Amino-4-(imidazole-4'-yl)-butyric H- 3 -HHis-OH acid H- 3 -HPhe-OH (3S)-3-Amino-4-phenyl butyric acid H- 3 -HTrp-OH (3S)-3-Amino-4-(indol-3'-yl)-butyric acid H- 3 -HSer-OH (3R)-3-Amino-4-hydroxy-butyric acid H- 3 -HAsp-OH 3-Amino-pentanedioic acid H- 3 -HGlu-OH (3S)-3-Amino-hexanedioic acid WO 2011/015241 PCT/EP2009/060168 509 Code Chemical Name H-P3-HLys-OH (3S) -3, 7-Diamino-heptanoic acid H-P3-HArg-OH (3S) -3-Amino-6-guanidino-hexanoic-acid H- 3 -HCys-OH (3R) -3-Amino-4-mercapto-butyric acid H- 3 -HAsn-OH (3S) -3-Amino-4-carbamoyl-butyric acid H- 3 -HGln-OH (3S) -3-Amino-5-carbamoyl-pentanoic acid H- 3 -HThr-OH (3R, 4R) -3-Amino-4-hydroxy-pentanoic acid Gaba 4-Amino-butyric acid H-. 4 -DiHAla-OH (4S)-4-Amino-pentanoic acid H-. 4 -DiHVal-OH (4R)-4-Amino-5-methyl-hexanoic acid H-. 4 -DiHIle-OH (4R, 5S)-4-Amino-5-methyl-heptanoic acid H-. 4 -DiHLeu-OH (4R)-4-Amino-6-methyl-heptanoic acid H-. 4 -DiHMet-OH (4R) -4-Amino-6-methylthio-hexanoic acid 4 (4R) -4-Amino-5- (4' -hydroxyphenyl) pentanoic acid H- 4 .DiHHis-OH (4R) -4-Amino-5- (imidazole-4' -yl) pentanoic acid H-. 4 -DiHPhe-OH (4R)-4-Amino-5-phenyl-pentanoic acid 4 (4R) -4-Amino-5- (indol-3' -yl) -pentanoic H-- -DiHTrp-OH ai acid H-. 4 -DiHSer-OH (4R)-4-Amino-5-hydroxy-pentanoic acid H-. 4 -DiHAsp-OH (4R)-4-Amino-hexanedioic acid H-. 4 -DiHGlu-OH 4-Amino-heptanedioic acid H-. 4 -DiHLys-OH (4S)-4,8-Diamino-octanoic acid H-. 4 -DiHArg-OH (4S) -4-Amino-7-guanidino-heptanoic-acid H-. 4 -DiHCys-OH (4R) -4-Amino-5-mercapto-pentanoic acid H-. 4 -DiHAsn-OH (4R) -4-Amino-5-carbamoyl-pentanoic acid H-. 4 -DiHGln-OH (3S) -3-Amino-5-carbamoyl-hexanoic acid H-. 4 -DiHThr-OH (4R, 5R)-4-Amino-5-hydroxy- hexanoic acid Cit L-Citrulline DCit D-Citrulline Orn L-Ornithine DOrn D-Ornithine tBuA L-t-Butylalanine DtBuA D-t-Butylalanine Sar Sarcosine Pen L-Penicillamine WO 2011/015241 PCT/EP2009/060168 510 Code Chemical Name D Pen D-Penicillamine tBuG L-tert.-Butylglycine D tBuG D-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine D 4AmPhe D-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine D 3AmPne D-meta-Aminophenylalanine 2AmPhe L-ortho-Aminophenylalanine D 2AmPhe D-ortho-Aminophenylalanine Phe (inC (NH 2 ) =NH) L-meta-Amidinophenylalanine D Phe (inC (NH 2 ) =NH) D-ineta-Aiidinophenylalanine Phe (pC (NH 2 ) =NH) L-para-Ainidinophenylalanine D Phe (pC (NH 2 ) =NH) D-para-Ainidinophenylalanine Phe (inNHC (NH 2 ) =NH) L-ieta-Guanidinophenylalanine D Phe (inNHC (NH 2 ) =NH) D-ieta-Guanidinophenylalanine Phe (pNHC (NH 2 ) =NH) L-para-Guanidinophenylalanine D Phe (pNHC (NH 2 ) =NH) D-para-Guanidinophenylalanine 2Pal (25) -2-Amino-3- (pyridine-2' -yl) -propionic 2Pal acid D 2Pal (2R) -2-Amino-3- (pyridine-2' -yl) -propionic acid (2S) -2-Amino-3- (pyridine-4' -yl) -propionic 4Pal acid D4a (2R) -2-Amino-3- (pyridine-4' -yl) -propionic 4Pal acid Phg L-Phenylglycine D Phg D-Phenylglycine Cha L-Cyclohexylalanine D Cha D-Cyclohexylalanine C 4 al L-3-Cyclobutylalanine D C 4 a1 D-3-Cyclobutylalanine C 5 al L-3-Cyclopentylalanine D C 5 a1 D-3-Cyclopentylalanine NMe L-Norleucine DNMe D-Norleucine 2-Nal L-2-Naphthylalanine D 2Na1 D-2-Naphthylalanine WO 2011/015241 PCT/EP2009/060168 511 Code Chemical Name 1-Nal L-1-Naphthylalanine D1Nal D-1-Naphthylalanine 4ClPhe L-4-Chlorophenylalanine D4ClPhe D-4-Chlorophenylalanine 3ClPhe L-3-Chlorophenylalanine D3ClPhe D-3-Chlorophenylalanine 2ClPhe L-2-Chlorophenylalanine D2ClPhe D-2-Chlorophenylalanine 3, 4C12Phe L-3,4-Dichlorophenylalanine D 3 , 4C12Phe D-3,4-Dichlorophenylalanine 4FPhe L-4-Fluorophenylalanine D4FPhe D-4-Fluorophenylalanine 3FPhe L-3-Fluorophenylalanine D3FPhe D-3-Fluorophenylalanine 2FPhe L-2-Fluorophenylalanine D2FPhe D-2-Fluorophenylalanine Thi L-P-2-Thienylalanine DThi D-P-2-Thienylalanine Tza L-2-Thiazolylalanine DTza D-2-Thiazolylalanine Mso L-Methionine sulfoxide DMSO D-Methionine sulfoxide AcLys N-Acetyllysine DAcLys N-Acetyl-D-lysine Dap 2,3-Diaminopropionic acid DDap D-2,3-Diaminopropionic acid Dab 2,4-Diaminobutyric acid DDab (2R)-2,4-Diaminobutyric acid Dbu (2S)-2,3-Diamino-butyric acid DDbu (2R)-2,3-Diamino-butyric acid Abu y-Aminobutyric acid (GABA) Aha --Aminohexanoic acid Aib .-Aminoisobutyric acid Cyp 1-Amino cyclopentane carboxylic acid Y(Bzl) L-0-Benzyltyrosine DY(Bzl) D-0-Benzyltyrosine WO 2011/015241 PCT/EP2009/060168 512 Code Chemical Name (3S)-2-Amino-3-(l'-benzylimidazole-4' yl)-propionic acid D (3R)- 2-Amino-3-(1'-benzylimidazole-4' yl)-propionic acid Bip L-(4-phenyl)phenylalanine DBip D-(4-phenyl)phenylalanine S(Bzl) L-0-Benzylserine DS (Bzl) D-0-Benzylserine T(Bzl) L-0-Benzylthreonine DT(Bzl) D-0-Benzylthreonine alloT (2S, 3S)-2-Amino-3-hydroxy-butyric acid DalloT (2R, 3S)-2-Amino-3-hydroxy-butyric acid (2S, 3R)-2-Amino-3-hydroxy-4-methyl pentanoic acid D Leu3H (2R, 3R)-2-Amino-3-hydroxy-4-methyl pentanoic acid hAla L-Homo-alanine DhAla D-Homo-alanine hArg L-Homo-arginine DhArg D-Homo-arginine hCys L-Homo-cysteine DhCys D-Homo-cysteine hGlu L-Homo-glutamic acid DhGlu D-glutamic acid hGln L-Homo-glutamine DhGln D-Homo-glutamine hHis L-Homo-histidine DhHis D-Homo-histidine hIle L-Homo-isoleucine DhIle D-Homo-isoleucine hLeu L-Homo-leucine DhLeu D-Homo-leucine hNle L-Homo-norleucine DhNle D-Homo-norleucine hLys L-Homo-lysine DhLys D-Homo-lysine hMet L-Homo-Methionine DhMet D-Homo-Methionine WO 2011/015241 PCT/EP2009/060168 513 Code Chemical Name hPhe L-Homo-phenylalanine DhPhe D-Homo-phenylalanine hSer L-Homo-serine DhSer D-Homo-serine hThr L-Homo-threonine DhThr D-Homo-threonine hTrp L-Homo-tryptophan DhTrp D-Homo-tryptophan hTyr L-Homo-tyrosine DhTyr D-Homo-tyrosine hVal L-Homo-valine DhVal D-Homo-valine hCha L-Homo-cyclohexylalanine DhCha D-Homo-cyclohexylalanine Bpa L-4-Benzoylphenylalanine DBpa D-4-Benzoylphenylalanine OctG L-Octylglycine DOctG D-Octylglycine . (3S)-1,2,3,4-Tetrahydroisoquinoline-3 carboxylic acid D . (3R)-1,2,3,4-Tetrahydroisoquinoline-3 carboxylic acid (iS)-1,2,3,4-Tetrahydroisoquinoline-1 carboxylic acid D (1R)-1,2,3,4-Tetrahydroisoquinoline-1 carboxylic acid (2S, 3aS, 7aS)-1-Octahydro-1H-indole-2 carboxylic acid DOic (2R, 3aS, 7aS)-1-Octahydro-1H-indole-2 carboxylic acid (2S, 4S)-4-Amino-pyrrolidine-2-carboxylic 4AmPyrrl ai acid D (2R, 4S)-4-Amino-pyrrolidine-2-carboxylic 4AmPyrrl ci acid (2S, 4R)-4-Amino-pyrrolidine-2-carboxylic D4AmPyrr2 ai acid D 4Am~yrr2 (2R, 4R)-4-Amino-pyrrolidine-2-carboxylic D4AmPyrr2 abxlcai acid (2S, 4R)-4-Phenyl-pyrrolidine-2 carboxylic acid D 4hyrl(2R, 4R)-4-Phenyl-pyrrolidine-2 carboxylic acid 4Pheyrr2(2S, 4S)-4-Phenyl-pyrrolidine-2 carboxylic acid WO 2011/015241 PCT/EP2009/060168 514 Code Chemical Name D (2R, 4S)-4-Phenyl-pyrrolidine-2 carboxylic acid (2S, 5R)-5-Phenyl-pyrrolidine-2 carboxylic acid D (2R, 5R)-5-Phenyl-pyrrolidine-2 carboxylic acid (2S, 5S)-5-Phenyl-pyrrolidine-2 carboxylic acid D (2R, 5S)-5-Phenyl-pyrrolidine-2 carboxylic acid 4Hypl (4S)-L-Hydroxyproline D4Hyp1 (4S)-D-Hydroxyproline 4Hyp2 (4R)-L-Hydroxyproline D4Hyp2 (4R)-D-Hydroxyproline 4Mpl (4S)-L-Mercaptoproline D4Mpl (4S)-D-Mercaptoproline 4Mp2 (4R)-L-Mercaptoproline D4Mp2 (4R)-D-Mercaptoproline Pip L-Pipecolic acid DPip D-Pipecolic acid H- 3 -HCit-OH (3S)-3-Amino-6-carbamidyl-hexanoic acid H- 3 -HOrn-OH (3S)-3,6-Diamino-hexanoic acid H- 3-HtBuA-OH (3S)-3-Amino-5,5-dimethyl-hexanoic acid H- 3 -HSar-OH N-Methyl-3-amino-propionic acid (3R)-3-Amino-4-methyl-4-mercapto H-1-HPen-OH pentanoic acid H- 3 -HtBuG-OH (3R)-3-Amino-4,4-dimethyl-pentanoic acid (3S)-3-Amino-4-(4'-aminophenyl)-butyric H-1 3 -H4AmPhe-OH acid (3S)-3-Amino-4-(3'-aminophenyl)-butyric H-1 3 -H3AmPhe-OH acid (3S)-3-Amino-4-(2'-aminophenyl)-butyric H-1 3 -H2AmPhe-OH acid H- 3 - (3S)-3-Amino-4-(3'-amidinophenyl)-butyric HPhe (mC (NH 2 ) =NH) -OH acid H- 3 - (3S)-3-Amino-4-(4'-amidinophenyl)-butyric HPhe (pC (NH 2 ) =NH) -OH acid H- 3 - (3S)-3-Amino-4-(3'-guanidinophenyl) HPhe (mNHC (NH 2 ) =NH) -OH butyric acid H- 3 - (3S)-3-Amino-4-(4'-guanidino-phenyl) HPhe (pNHC (NH 2 ) =NH) -OH butyric acid (3S)-3-Amino-4-(pyridine-2'-yl)-butyric H-1-H2Pal-OH acid WO 2011/015241 PCT/EP2009/060168 515 Code Chemical Name (3S)-3-Amino-4-(pyridine-4'-yl)-butyric H- 3 -H4Pal-OH acid H- 3 -HPhg-OH (3R)-3-Amino-3-phenyl-propionic acid H- 3 -HCha-OH (3S)-3-Amino-4-cyclohexyl-butyric acid H- 3 -HC 4 al-OH (3S)-3-Amino-4-cyclobutyl-butyric acid H- 3 -HCsal-OH (3S)-3-Amino-4-cyclopentyl-butyric acid H- 3 -HN1e-OH (3S)-3-Amino-heptanoic acid H- 3 -H2Na1-OH (3S)-3-Amino-4-(2'-naphthyl)-butyric acid H- 3 -H1Nal-OH (3S)-3-Amino-4-(l'-naphthyl)-butyric acid (3S)-3-Amino-4-(4'-chlorophenyl)-butyric H- 3 -H4ClPhe-OH acid (3S)-3-Amino-4-(3'-chlorophenyl)-butyric H- 3 -H3ClPhe-OH acid (3S)-3-Amino-4-(2'-chlorophenyl)-butyric H- 3 -H2ClPhe-OH acid (3S)-3-Amino-4-(3',4'-dichlorophenyl) H-1-H3, 4Cl 2 Phe-OH butyric acid (3S)-3-Amino-4-(4'-fluorophenyl)-butyric H- 3 -H4FPhe-OH acid (3S)-3-Amino-4-(3'-fluorophenyl)-butyric H- 3 -H3FPhe-OH acid (3S)-3-Amino-4-(2'-fluorophenyl)-butyric H- 3 -H2FPhe-OH acid H- 3 -HThi-OH (3R)-3-Amino-4-(2'-thienyl)-butyric acid (3R)-3-Amino-4-(2'-thiazolyl)-butyric H- 3 -HTza-OH acid (3R)-3-Amino-4-methylsulfoxyl-butyric H- 3 -HMso-OH acid H- 3 -HAcLys-OH (3S)-7-Acetylamino-3-amino-heptanoic acid H- 3-HDpr-OH (3R)-3,4-diamino-butyric acid H- 3 -HA 2 Bu-OH (3S)-3,5-Diamino-pentanoic acid H- 3 -HDbu-OH (3R)-3,4-Diamino-pentanoic acid H- 3 -HAib-OH Amino-dimethyl acetic acid H- 3 -HCyp-OH 1-Amino-cyclopentane-1-yl-acetic acid (3S)-3-Amino-4-(4'-benzyloxyphenyl) H-1-HY(Bzl)-OH butyric acid (3S)-3-Amino-4-(1'-benzylimidazole-4' H-1-HH(Bzl)-OH yl)-butyric acid H- 3 -HBip-OH (3S)-3-Amino-4-biphenylyl-butyric acid H- 3 -HS(Bzl)-OH (3S)-3-Amino-4-(benzyloxy)-butyric acid (3R, 4R)-3-Amino-4-benzyloxy-pentanoic H- -HT (Bzl)-OH acid WO 2011/015241 PCT/EP2009/060168 516 Code Chemical Name H-P3-HalloT-OH (3R, 4S) -3-Amino-4-hydroxy-pentanoic acid (3R, 4R) -3-Amino-4-hydroxy-5-methyl H-1 3 -HLeu30H-OH hexanoic acid H- 3 -HhAla-OH (3S) -3-Amino-pentanoic acid H- 3 -HhArg-OH (3S) -3-Amino-7-guanidino-heptanoic acid H- 3 -HhCys-OH (3R) -Amino-5-mercapto-pentanoic acid H- 3 -HhGlu-OH (3S) -3-Amino-heptanedioic acid H- 3 -HhGln-OH (3S)-3-Amino-6-carbamoyl hexanoic acid - . _(3S) -3-Amino-5- (imidazole-4' -yl) H-1-HhHis-OH pentanoic acid H- 3 -HhIle-OH (3S, 5S) -3-Amino-5-methyl-heptanoic acid H- 3 -HhLeu-OH (3S) -3-Amino-6-methyl-heptanoic acid H- 3 -HhNle-OH (3S)-3-Amino-octanoic acid H- 3 -DiAoc-OH (3S) -3, 8-Diamino-octanoic acid H- 3 -HhMet-OH (3S) -3-Amino-6-methylthio-hexanoic acid H- 3 -HhPe-OH (3S) -3-Amino-5-phenyl-pentanoic acid H- 3-HhSer-OH (3S) -3-Amino-5-hydroxy-pentanoic acid H- 3-HhThr-OH (3S, 5R) -3-Amino-5-hydroxy-hexanoic acid (3S) -3-Amino-5- (indol-3' -yl) -pentanoic H-1-HhTrp-OH acid (3S) -3-Amino-5- (4' -hydroxyphenyl) H-1-HhThr-OH pentanoic acid H- 3-HhCha-OH (3S) -3-Amino-5-cyclohexyl-pentanoic acid (3S) -3-Amino-4- (4' -benzoylphenyl) -butyric H-1 3 -HBpa-OH acid H- 3-HOctG-OH (3S) -3-Amino-undecanoic acid H- 3 -HN1e-OH (3S) -3-Amino-heptanoic acid 3 . (3S)-1,2,3,4-Tetrahydroisoquinoline-3-yl H-1-HTic-OH acetic acid 3 . (S)-1,2,3,4-Tetrahydroisoquinoline-1 H-1-HTiq-OH acetic acid 3 . (2S, 3aS, 7aS)-1-Octahydro-1H-indole-2 H-1-HOic-OH yl-acetic acid (2S, 4S) -4-Amino-pyrrolidine-2-acetic H-1-H4AmPyrrl-OH acid (2S, 4R) -4-Amino-pyrrolidine-2-acetic H-1-H4AmPyrr2-OH acid (2S, 4R)-4-Phenyl-pyrrolidine-2-acetic H-1-H4PhePyrrl-OH acid (2S, 4S)-4-Phenyl-pyrrolidine-2-acetic H-1-H4PhePyrr2-OH acid WO 2011/015241 PCT/EP2009/060168 517 Code Chemical Name (2S, 5R)-5-Phenyl-pyrrolidine-2-acetic H- 3 -H5PhePyrr1-OH acid (2S, 5S)-5-Phenyl-pyrrolidine-2-acetic H- 3 -H5PhePyrr2-OH acid (2S, 4S)-4-Hydroxy-pyrrolidine-2-acetic H- 3 -H4Hypl-OH acid (2S, 4R)-4-Hydroxy-pyrrolidine-2-acetic H- 3 -H4Hyp2-OH acid (2R, 4S)-4-Mercapto-pyrrolidine-2-acetic H- 3 -H4Mpl-OH acid (2R, 4R)-4-Mercapto-pyrrolidine-2-acetic H- 3 -H4Mp2-OH acid H- 3 -HPip-OH (2S) -piperidine-2-acetic acid H- 3 -HPro-OH (2S) -pyrrolidine-2-acetic acid H p 3 -HDPro-OH (2R) -pyrrolidine-2-acetic acid Ahb 4-Amino-2-hydroxy butyric acid H-- 4 -DiHCit-OH (4S) -4-Amino-7-carbamidyl-heptanoic acid H-- -DiHOrn-OH (4S)-4,7-Diamino-heptanoic acid H-- 4 -DiHtBuA-OH (4R) -4-Amino-6, 6-dimethyl-heptanoic acid H-- -DiHSar-OH N-Methyl-4-amino-butyric acid 4 (4R) -4-Amino-5-methyl-5-mercapto-hexanoic H- - -DiHPen-OH ai acid H- -4-DiHtBuG-OH (4R) -4-Amino-5, 5-dimethyl-hexanoic acid 4 (4R) -4-Amino-5- (4' -aminophenyl) -pentanoic H- - -DiH4AmPhe-OH ai acid 4 (4R) -4-Amino-5- (3' -aminophenyl) -pentanoic H- - -DiH3AmPhe-OH ai acid 4 (4R) -4-Amino-5- (2' -aminophenyl) -pentanoic H- - -DiH2AmPhe-OH ai acid H-- 4- (4R)-4-Amino-5-(3'-amidinophenyl) DiHPhe (mC (NH 2 ) =NH) -OH pentanoic acid H-- 4- (4R) -4-Amino-5- (4' -amidinophenyl) DiHPhe (pC (NH 2 ) =NH) -OH pentanoic acid H- - 4 (4R) -4-Amino-5- (3' -guanidino-phenyl) DiHPhe (mNHC (NH 2 ) =NH)- pentanoic acid OH H- - (4R) -4-Amino-5- (4' -guanidino-phenyl) DiHPhe (pNHC (NH 2 ) =NH)- pentanoic acid OH H-4 -- DiH2Pa1-OH (4R) -4-Amino-5- (pyridine-4' -yl) -pentanoic acid 4 (4R) -4-Amino-5- (pyridine-4' -yl) -pentanoic H-- -DiH4Pa-OH acid H-- 4 -DiHPhg-OH (4R)-4-Amino-4-phenyl-butyric acid H-- 4 -DiHCha-OH (4R) -4-Amino-5-cyclohexyl-pentanoic acid WO 2011/015241 PCT/EP2009/060168 518 Code Chemical Name H-- -DiHC 4 al-OH (4R)-4-Amino-5-cyclobutyl-pentanoic acid H-- -DiHC 5 al-OH (4R)-4-Amino-5-cyclopentyl-pentanoic acid H-- 4 -DiHNle-OH (4S)-4-Amino-octanoic acid 4 (4S)-4-Amino-5-(2'-naphthyl)-pentanoic H- - -DiH2Nal-OH ai acid 4 (4S)-4-Amino-5-(l'-naphthyl)-pentanoic H- - -DiH1Pal-OH pnaocai acid 4 (4R)-4-Amino-5-(4'-chlorophenyl) pentanoic acid H- 4 -DiH2C1Phe-OH (4R)-4-Amino-5-(3'-chlorophenyl) pentanoic acid 4 (4R)-4-Amino-5-(2'-chlorophenyl) H-- -DiH2,ClPhe-OH pnaocai pentanoic acid 4 (4R)-4-Amino-5-(3',4'-dichloro-phenyl) pentanoic acid H-- 4 -DiH2FPhe-OH (4R)-4-Amino-5-(4'-fluorophenyl) pentanoic acid 4 (4R)-4-Amino-5-(3'-fluorophenyl) H- - -DiH3Fh-OH ai pentanoic acid 4 (4R)-4-Amino-5-(2'-fluorophenyl) H- - -DiHFzh-OH ai pentanoic acid H- . 4 -DiH~so-OH (4R)-4-Amino-5-(2'-thienyl)-pentanoic acid H- 4 DiHA-OH (4R)-4-Amino-5-(2'- thiazolyl)-pentanoic acid H.4_isoO (4R)-4-Amino-5-methylsulfoxyl-pentanoic acid H-- 4 -DiHAcLys-OH (4S)-8-Acetylamino-ocatanoic acid H-- 4 -DiHDpr-OH (4R)-4,5-diamino-pentanoic acid H-- 4 -DiHA2Bu-OH (4R)-4,5-Diamino-hexanoic acid H-- 4-DiHDbu-OH (4R)-4,5-Diamion-hexanoic acid H-- 4 -DiHAib-OH 3-Amino-3,3-dimethyl propionic acid 4 (1'-Amino-cyclopentane-l'-yl)-3-propionic H- - -DiHCyp-OH ai acid 4 (4R)-4-Amino-5-(4'-benzyloxyphenyl) H-- -DiHY(Bzl)-OH pnaocai pentanoic acid 4 (4R)-4-Amino-5-(1'-benzylimidazole-4' yl)-pentanoic acid H-- 4 -DiHBip-OH (4R)-4-Amino-5-biphenylyl-pentanoic acid H-- 4 -DiHS(Bzl)-OH (4S)-4-Amino-5-(benzyloxy)-pentanoic acid 4 (4R, 5R)-4-Amino-5-benzyloxy-hexanoic H-- -DiHT(Bzl)-OH ai acid H-- 4 -DiHalloT-OH (4R, 5S)-4-Amino-5-hydroxy-hexanoic acid 4 (4R, 5R)-4-Amino-5-hydroxy-6-methyl H-- -DiHLeu3H-OH heptanoic acid WO 2011/015241 PCT/EP2009/060168 519 Code Chemical Name H-. 4 -DiHhAla-OH (4S)-4-Amino-hexanoic acid H-. 4 -DiHhArg-OH (4S)-4-Amino-8-guanidino-octanoic acid H-. 4 -DiHhCys-OH (4R)-Amino-6-mercapto-hexanoic acid H-. 4 -DiHhGlu-OH (4S)-4-Amino-ocatanedioic acid H-. 4 -DiHhGln-OH (4S)-4-Amino-7-carbamoyl-heptanoic acid H-. 4 _DiHhHis-OH (4S)-4-Amino-6-(imidazole-4'-yl)-hexanoic acid H-. 4 -DiHhIle-OH (4S, 6S)-4-Amino-6-methyl-octanoic acid H-. 4 -DiHhLeu-OH (4S)-4-Amino-7-methyl-ocatanoic acid H-. 4 -DiHhNle-OH (4S)-4-Amino-nonanoic acid H-. 4 -DiHhLys-OH (4S)-4,9-Diamino-nonanoic acid H-. 4 -DiHhMet-OH (4R)-4-Amino-7-methylthioheptanoic acid H-. 4 -DiHhPhe-OH (4S)-4-Amino-6-phenyl-hexanoic acid H-. 4 -DiHhSer-OH (4R)-4-Amino-6-hydroxy-hexanoic acid H-. 4 -DiHhThr-OH (4R, 6R)-4-Amino-6-hydroxy-heptanoic acid 4 (4S)-4-Amino-6-(indol-3'-yl)-hexanoi H-- -DiHhTrp-OH cai cacid 4 (4S)-4-Amino-6-(4'-hydroxyphenyl) H-- -DiHhTyr-OH heaocci hexanoic acid H-. 4 -DiHhCha-OH (4R)-4-Amino-5-cyclohexyl-pentanoic acid 4 (4R)-4-Amino-5-(4'-benzoylphenyl) pentanoic acid H-. 4 -DiHOctG-OH (4S)-4-Amino-dodecanoic acid H-. 4 -DiHNle-OH (4S)-4-Amino-octanoic acid H-. 4 -DiHTic-OH (3R)-l',2',3',4'-Tetrahydroisoquinoline 3'-yl-3-propionic acid 4 . (1'R)-l',2',3',4'-Tetrahydroisoquinoline l'-yl-3-propionic acid 4 . (2'S, 3'aS, 7'aS)-1'-Octahydro-1H-indole 2'-yl-3-propionic acid 4 _ (2'R, 4'S)-4'-Amino-pyrrolidine-2'-yl-3 H- DiH4AmPyrrl-OH poincai H-. propionic acid 4 (2'R, 4'R)-4'-Amino-pyrrolidine-2'-yl-3 H-- -DiH4AmPyrr2-OH poincai propionic acid 4 (2'R, 4'R)-4'-Phenyl-pyrrolidine-2'-yl-3 H-- -DiH4PhePyrrl-OH propionic acid 4 (2'R, 4'S)-4'-Phenyl-pyrrolidine-2'-yl-3 H-- -DiH4PhePyrr2-OH poincai propionic acid 4 (2'S, 5'R)-5'-Phenyl-pyrrolidine-2'-yl-3 H-- -DiH5PhePyrrl-OH propionic acid 4 (2'S, 5'S)-5'-Phenyl-pyrrolidine-2'-yl-3 H- -DiH5PhePyrr2-OHacid WO 2011/015241 PCT/EP2009/060168 520 Code Chemical Name 4 (2'R, 4'S)-4'-Hydroxy-pyrrolidine-2'-yl 2-propionic acid 4 (2'R, 4'R)-4'-Hydroxy-pyrrolidine-2'-yl 3-propionic acid 4 (2'R, 4'S)-4'-Mercapto-pyrrolidine-2'-yl 3-propionic acid 4 (2'R, 4'R)-4'-Mercapto-pyrrolidine-2'-yl 3-propionic acid H-. 4 -DiHPip-OH (2'S)-Piperidine-2'-yl-3-propionic acid H-. 4 -DiHPro-OH (2'S)-Pyrrolidine-2'-yl-3-propionic acid (AEt)G N-(2-Aminoethyl)glycine (APr) G N- (3-Amino-n-propyl) glycine (ABu) G N- (4-Amino-n-butyl) glycine (APe) G N- (5-Amino-n-pentyl) glycine (GuEt)G N-(2-Guanidinoethyl)glycine (GuPr)G N-(3-Guanidino-n-propyl)glycine (GuBu)G N-(4-Guanidino-n-butyl)glycine (GuPe)G N-(5-Guanidino-n-pentyl)glycine (PEG 3 -NH2) G N- [H2N- (CH2) 3- (OCH 2 -CH 2 ) 2-0 (CH 2 ) 31 glycine (Me) G N-Methylglycine (Et)G N-Ethylglycine (Bu)G N-Butylglycine (Pe)G N-Pentylglycine (Ip)G N-Isopropylglycine (2MePr)G N-(2-Methylpropyl)glycine (3MeBu)G N-(3-Methylbutyl)glycine (lMePr)G (1S)-N-(1-Methylpropyl)glycine (2MeBu)G (2S)-N-(2-Methylbutyl)glycine (MthEt)G N-(Methylthioethyl)glycine (MthPr)G N-(Methylthiopropyl)glycine (Ben)G N-(Benzyl)glycine (PhEt)G N-(2-Phenylethyl)glycine (HphMe)G N-([4'-hydroxyphenylimethyl)glycine (HphEt)G N-(2-[4'-hydroxyphenyl]ethyl)glycine (ImMe)G N-(Imidazol-5-yl-methyl)glycine (ImEt)G N-(2-(Imidazol-5'-yl)ethyl)glycine (InMe)G N-(Indol-2-yl-methyl)glycine (InEt)G N-(2-(Indol-2'-yl)ethyl)glycine (CboMe)G N-(Carboxymethyl)glycine (CboEt)G N-(2-Carboxyethyl)glycine (CboPr)G N-(3-Carboxypropyl)glycine WO 2011/015241 PCT/EP2009/060168 521 Code Chemical Name (CbaMe) G N- (Carbamoylmethyl) glycine (CbaEt) G N- (2-Carbamoylethyl) glycine (CbaPr) G N- (3-Carbamoylpropyl) glycine (HyEt) G N- (2-Hydroxyethyl) glycine (HyPr) G (2R) -N- (2-Hydroxypropyl) glycine (Mcet) G N- (2-Mercaptoethyl) glycine NMeAla L-N-Methylalanine NMe DAla D-N-Methylalanine NMeVa1 L-N-Methylvaline NMe DVal D-N-Methylvaline NMeIle L-N-Methylisoleucine NMe DI le D-N-Methylisoleucine NMeLeu L-N-Methylleucine NMe D Leu D-N-Methylleucine NMeNle L-N-Methylnorleucine NMe D Ne D-N-Methylnorleucine NMeMet L-N-Methylmethionine NMe D Met D-N-Methylmethionine NMeTyr L-N-Methyltyrosine NMe DTyr D-N-Methyltyrosine NMeHis L-N-Methylhistidine NMe D His D-N-Methylhistidine NMePhe L-N-Methylphenylalanine NMe DPhe D-N-Methylphenylalanine NMeTrp L-N-Methyltryptophane NMe D Tp D-N-Methyltryptophane NMeSer L-N-Methylserine NMe D Ser D-N-Methylserine NMeAsp L-N-Methylaspartic acid NMe DAsp D-N-Methylaspartic acid NMeGlu L-N-Methylglutamic acid NMe D Gu D-N-Methylglutamic acid NMeLys L-N-Methyllysine NMe DLys D-N-Methyllysine NMeArg L-N-Methylarginine NMe DArg D-N-Methylarginine NMeDab L-N-Methyl-2,4-diamino butyric acid WO 2011/015241 PCT/EP2009/060168 522 Code Chemical Name NMeDDab D-N-Methyl-2,4-diamino butyric acid NMeCys L-N-Methylcysteine NMeDCys D-N-Methylcysteine NMeAsn L-N-Methylasparagine NMe DAsn D-N-Methylasparagine NMeGln L-N-Methylglutamine NMeDGln D-N-Methylglutamine NMeThr L-N-Methylthreonine NMeDThr D-N-Methylthreonine
6. Compounds according to claim 1, selected from: (2S,11S,19aS)-2-(acetylamino)-15-fluoro-N-[2-(1H-indol-3 5 yl)ethyl]-7,12-dimethyl-5,8,13-trioxo 2,3,6,7,8,9,10,11,12,13,19,19a-dodecahydro-1H,5H pyrrolo[2,1-c][1,4,7,12]benzoxatriazacyclopentadecine-11 carboxamide; (2S,11S,19aS)-N-[2-(dimethylamino)ethyl]-15 fluoro-2-{[2-(1H-indol-3-yl)acetyl]amino}-7,12-dimethyl 10 5,8,13-trioxo-2,3,6,7,8,9,10,11,12,13,19,19a-dodecahydro 1H,5H-pyrrolo[2,1-c][1,4,7,12]benzoxatriazacyclopentadecine
11-carboxamide; (2S,11S,19aS)-15-fluoro-2-{[2-(1H-indol-3 yl)acetyl]amino}-N-[2-(1H-indol-3-yl)ethyl]-7,12-dimethyl 5,8,13-trioxo-2,3,6,7,8,9,10,11,12,13,19,19a-dodecahydro 15 1H,5H-pyrrolo[2,1-c][1,4,7,12]benzoxatriazacyclopentadecine 11-carboxamide; (2S,11S,19aS)-2-{[2 (dimethylamino)acetyl]amino}-15-fluoro-N-[2-(1H-indol-3 yl)ethyl]-7,12-dimethyl-5,8,13-trioxo 2,3,6,7,8,9,10,11,12,13,19,19a-dodecahydro-1H,5H 20 pyrrolo[2,1-c][1,4,7,12]benzoxatriazacyclopentadecine-11 carboxamide; tert-butyl N-[(2S,11S,19aS)-15-fluoro-11-({[2 (1H-indol-3-yl)ethyl]aminolcarbonyl)-7,12-dimethyl-5,8,13 trioxo-2,3,6,7,8,9,10,11,12,13,19,19a-dodecahydro-1H,5H pyrrolo[2,1-c][1,4,7,12]benzoxatriazacyclopentadecin-2 25 yl]carbamate; (2S,11S,19aS)-N-[2-(dimethylamino)ethyl]-15 fluoro-7,12-dimethyl-2-{[2-(1-naphthyl)acetyl]amino}-5,8,13- WO 2011/015241 PCT/EP2009/060168 523 trioxo 2,3,6,7,8,9,10,11,12,13,19,19a-dodecahydro-1H,5H pyrrolo[2,1-c][1,4,7,12]benzoxatriazacyclopentadecine-11 carboxamide; benzyl N-[(4S,6S,10S)-14-methyl-6-{[2-(2 5 naphthyl)acetyl]amino}-9,15-dioxo-2-oxa-8,14 diazatricyclo[14.3.1.0~4,8~]icosa-1(20),16,18-trien-10 yl]carbamate; benzyl N-[(4S,6S,13S)-6-{[2-(1H-indol-3 yl)acetyl]aminol-11,15-dimethyl-9,12,16-trioxo-2-oxa 8,11,15-triazatricyclo[15.3.1.0-4,8-]henicosa-1(21),17,19 10 trien-13-yl]carbamat; N-[(4S,6S,13S)-6-{[2-(1H-indol-3 yl)acetyl]aminol-11,15-dimethyl-9,12,16-trioxo-2-oxa 8,11,15-triazatricyclo[15.3.1.04,8-]henicosa-1(21),17,19 trien-13-yl]decanamide. 15 7. Compounds according to any one of claims 1-6 for use as therapeutically active substances. 8. Compounds according to claim 7 for use as therapeutically active substances having agonistic or 20 antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT2B (5-HT2B receptor), and on the prostaglandin F2. receptor (FP receptor). 9. A pharmaceutical composition containing a compound 25 according to any one of claims 1-6 and a therapeutically inert carrier. 10. A composition according to claim 9 having agonistic or antagonistic activity on the motilin receptor (MR receptor), 30 on the serotonin receptor of subtype 5-HT2B (5-HT2B receptor), and on the prostaglandin F2. receptor (FP receptor). 11. A composition according to claim 9 or 10 in a form suitable for oral, topical, transdermal, injection, buccal, 35 transmucosal, pulmonary or inhalation administration. WO 2011/015241 PCT/EP2009/060168 524
12. Compositions according to claim 11 in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser or suppositories. 5
13. The use of compounds according to any one of claims 1-6 for the manufacture of a medicament having agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT2B (5-HT2B receptor), 10 and on the prostaglandin F2. receptor (FP receptor).
14. The use according to claim 13 wherein said medicament is intended for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis 15 and constipation type irritable bowl syndrome; for the treatment of CNS related diseases like migraine, schizophrenia, psychosis or depression; for the treatment of ocular hypertension such as associated with glaucoma and preterm labour. 20
15. The use of compounds according to anyone of claims 1-5 for pharmaceutical lead finding.
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